Acromegaly is a chronic endocrine disorder caused by excessive growth hormone secretion, usually from a pituitary adenoma, resulting in progressive enlargement of the hands, feet, and facial features along with systemic complications.

Exam domain	One-glance essentials
Definition / diagnosis	Chronic growth-hormone excess after epiphyseal fusion; before fusion it causes gigantism ^[1] *A GH-secreting pituitary adenoma accounts for > 95% of cases* ^[2]^[3]
Epidemiology / risks	Usually sporadic; consider MEN1, Carney complex or McCune-Albright syndrome in a syndromic or familial case ^[2] Delayed recognition is common because acral and facial change is gradual
Core mechanism	Pituitary GH excess → hepatic and local IGF-1 → soft-tissue, bone and organ growth ^[1]^[2] GH antagonises insulin and promotes sodium retention → diabetes and hypertension
Clinical picture	*Coarse facies, prognathism, macroglossia and increasing ring/shoe size* ^[3] Hyperhidrosis, carpal tunnel syndrome, OSA, headache and bitemporal hemianopia are key clues ^[2]^[3]
Investigations	Screen with age-adjusted IGF-1; random GH is unreliable ^[1]^[4] Confirm with 75-g OGTT: GH fails to suppress; then localise with contrast pituitary MRI ^[1]^[2] Assess all pituitary axes, visual fields, glucose, heart, sleep apnoea and colon ^[2]
Management	*First-line transsphenoidal surgery* for a resectable GH-secreting adenoma ^[2]^[5] Persistent disease: somatostatin analogue, pegvisomant or cabergoline; radiotherapy is delayed adjunctive therapy ^[1]^[2]
Complications	Hypertension, LVH/cardiomyopathy and heart failure drive excess mortality ^[2] Diabetes, OSA, irreversible arthropathy/CTS and increased colorectal-neoplasia risk ^[2]^[3]
Prevention / follow-up	After treatment, monitor IGF-1 and pituitary function and manage cardiovascular/metabolic risk ^[1]^[2] Colonoscopic and OSA surveillance should follow the patient’s risk and local protocol ^[2]^[3]
Exam traps	*Biochemistry before imaging: a pituitary incidentaloma does not prove acromegaly ^[4] Do not use random GH to screen; use IGF-1, then OGTT suppression ^[1]^[4] No pituitary lesion on MRI → consider ectopic GHRH* ^[2]

References

^[1] Senior notes: Maksim Medicine Notes.pdf (Acromegaly, p108) ^[2] Senior notes: Ryan Ho Endocrine.pdf (Acromegaly, p111) ^[3] Lecture slides: GC 067. I keep on bumping into people on my side.pdf ^[4] Senior notes: Block A - Introduction to Endocrine investigations.pdf, p1–8 ^[5] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf, p11

Acromegaly

Acromegaly — from Greek: akron (extremity) + megas (large) — is a chronic, insidious endocrine disorder characterised by excess growth hormone (GH) secretion in adults after epiphyseal plate fusion, resulting in progressive soft tissue overgrowth, acral (extremity) enlargement, and multi-organ complications ^[1]^[2].

When the same pathophysiology occurs before epiphyseal fusion in children, the result is gigantism — excess linear bone growth leading to abnormally tall stature ^[1].

Key Distinction (High Yield)

Acromegaly = GH excess in adults (after epiphyseal fusion) → cannot grow taller, so bones widen and soft tissues enlarge. Gigantism = GH excess in children (before epiphyseal fusion) → can still grow linearly → excessive height. This distinction is fundamental and frequently tested. ^[1]

Prevalence: Not as uncommon as previously thought — prevalence up to ~1 per 1,000 in newer population-based studies (previously quoted as 40–130 per million) ^[2]. Many cases go undiagnosed for years due to the insidious onset.
Incidence: Approximately 3–4 new cases per million population per year.
Age at diagnosis: Typically 40–50 years of age, but disease onset is often a decade or more earlier. The average delay from symptom onset to diagnosis is 7–10 years.
Sex: Roughly equal male-to-female ratio, though some series show a slight female preponderance.
Mortality: Overall mortality 1.72× that of the general population, mainly driven by cardiovascular disease ^[2]^[3]. Achieving biochemical control (normalising IGF-1 and GH) brings mortality back towards baseline.

In Hong Kong, pituitary adenomas (including GH-secreting adenomas) are managed at tertiary centres. Due to the insidious nature of the disease, many patients present with established complications (hypertension, diabetes, arthropathy).

Most cases are sporadic. Identifiable risk factors/associations include:

Risk Factor	Explanation
Sporadic pituitary adenoma	The overwhelming majority (~95%) — no identifiable familial syndrome
MEN-1 (Multiple Endocrine Neoplasia type 1)	Autosomal dominant; mutations in menin tumour suppressor gene (chr 11q13). Pituitary adenomas (including GH-secreting) occur alongside parathyroid hyperplasia and pancreatic neuroendocrine tumours ("3 Ps": Parathyroid, Pancreas, Pituitary) ^[1]
Carney complex	Autosomal dominant (PRKAR1A gene); characterised by cardiac myxoma, spotted skin pigmentation (lentigines, blue naevi), and pituitary adenomas (including GH-secreting) ^[1]
McCune-Albright syndrome	Somatic activating mutations in GNAS1 (Gsα subunit) → constitutive activation of cAMP signalling in somatotrophs. Classic triad: precocious puberty, café-au-lait spots (coast-of-Maine border), fibrous dysplasia of bone ^[1]
Familial isolated pituitary adenoma (FIPA)	AIP gene mutations; younger age at diagnosis, often macroadenomas
X-linked acrogigantism (X-LAG)	GPR101 gene duplication on Xq26.3; presents in infancy/childhood with gigantism

Disease Associations — High Yield for SAQ

MEN-1, Carney complex (cardiac myxoma, spotted skin pigmentation), McCune-Albright syndrome (precocious puberty, café-au-lait spots, fibrous dysplasia) — these are the three classic syndromic associations tested in exams ^[1].

Anatomy and Function: The Hypothalamic–Pituitary–GH/IGF-1 Axis

Understanding acromegaly requires a thorough grasp of the normal physiology of GH secretion and action.

The pituitary gland (hypophysis) sits in the sella turcica of the sphenoid bone.
Anterior pituitary (adenohypophysis): derived from Rathke's pouch (oral ectoderm). Contains five principal cell types:
- Somatotrophs (~50% of anterior pituitary cells) → secrete GH (somatotropin)
- Lactotrophs → PRL
- Corticotrophs → ACTH
- Thyrotrophs → TSH
- Gonadotrophs → FSH/LH
Posterior pituitary (neurohypophysis): neural ectoderm origin. Stores and releases ADH (AVP) and oxytocin from hypothalamic nuclei.

The posterior pituitary receives its blood supply from the vertebral artery (inferior hypophyseal artery) — i.e. systemic circulation — whereas the anterior pituitary receives its blood supply via the hypothalamic–hypophyseal portal system (superior hypophyseal artery). This is clinically relevant: metastases (systemic haematogenous spread) tend to affect the posterior pituitary first ^[4].

Immediately above the sella turcica lies the optic chiasm — this is why a suprasellar extension of a pituitary macroadenoma classically causes a bitemporal hemianopia (compression of the crossing nasal fibres of the optic chiasm). Laterally, the cavernous sinuses contain CN III, IV, V1, V2, and VI — lateral extension can cause cranial nerve palsies and diplopia ^[2]^[5].

Hypothalamic regulation:
- GHRH (Growth Hormone–Releasing Hormone): stimulates GH release from somatotrophs.
- Somatostatin (SST, also called GHIH — Growth Hormone–Inhibiting Hormone): inhibits GH release. This is the pharmacological target of somatostatin analogues (e.g. octreotide, lanreotide).
- Ghrelin (from the stomach): also stimulates GH release via the GH secretagogue receptor — links nutritional status with GH.
GH secretion pattern:
- GH is released in a pulsatile, episodic fashion with a diurnal rhythm — highest during deep sleep (stages 3–4 NREM), lowest during the day.
- GH is influenced by exercise, stress, sleep, and meals — this is why a random GH level is NOT useful for diagnosis ^[4].
- GH half-life is very short (~15–20 minutes).
GH actions — direct and indirect (via IGF-1):
- Direct effects: Lipolysis (↑free fatty acids), insulin resistance (counter-regulatory to insulin), hepatic gluconeogenesis.
- Indirect effects (via IGF-1): GH stimulates the liver (and other tissues) to produce IGF-1 (Insulin-like Growth Factor-1, also called somatomedin C). IGF-1 mediates most of the growth-promoting (anabolic) effects:
  - Soft tissue growth, chondrocyte proliferation, bone growth
  - Protein synthesis in muscle
  - Cell proliferation (which is why excess → ↑ cancer risk)
- IGF-1 has a much longer half-life (18–20 hours) and is relatively stable throughout the day → this is why serum IGF-1 is the preferred screening test ^[2]^[3]^[6].
Negative feedback: IGF-1 feeds back to both the hypothalamus (↑somatostatin) and the pituitary (↓GH release) to close the loop.

Why Random GH Is Not Useful

Random GH is highly variable depending on personal status (exercise, stress, sleep, pulsatility) and has a short half-life — it does not indicate much if interpreted by itself. ^[4] Instead, use IGF-1 (stable, reflects integrated 24-hour GH secretion) or GH during OGTT (dynamic suppression test).

In a healthy person, after an oral glucose load (75g OGTT):

Glucose → ↑insulin → suppresses GH secretion → GH falls to < 1 ng/mL (or < 0.4 ng/mL by newer assays).
In acromegaly, the autonomous GH secretion from the adenoma is NOT suppressible by glucose → GH remains elevated (or may even paradoxically increase in ~30% of cases) ^[2]^[3].

This is the basis of the oral glucose tolerance test (OGTT) as the gold standard diagnostic test for acromegaly ^[2]^[3]^[6].

Cause	Frequency	Notes
GH-secreting pituitary adenoma	> 95%	Somatotroph adenoma; may be micro ( < 1 cm) or macro ( > 1 cm). ~70% are macroadenomas at diagnosis. May co-secrete prolactin (~30%) ^[1]^[2]
GHRH-secreting hypothalamic ganglioneuroma/hamartoma	Rare	Excess GHRH → somatotroph hyperplasia → excess GH
Ectopic GH or GHRH secretion	Very rare	Neuroendocrine tumours (bronchial/pancreatic carcinoid), small cell lung cancer, lymphoma

Exam Favourite

Over 95% of acromegaly is caused by a GH-secreting pituitary adenoma. ^[1]^[2] Always think "pituitary adenoma" first when you encounter acromegaly in any clinical scenario.

Why Does a Pituitary Adenoma Form?

Somatotroph adenomas arise from monoclonal proliferation of a single mutated somatotroph cell. The most characterised somatic mutation is in GNAS1 (Gsα subunit) — found in ~40% of sporadic somatotroph adenomas. This mutation locks the Gsα protein in a constitutively active "on" state → ↑cAMP → ↑GH transcription and secretion, as well as ↑cell proliferation. This is the same gene affected in McCune-Albright syndrome (but somatically mosaic in that condition).

Co-secretion of prolactin (in ~30% of cases) occurs because:

Some adenomas are mammosomatotroph adenomas (producing both GH and PRL from the same cell)
Some GH-secreting adenomas physically compress the pituitary stalk → interrupting dopamine inhibition of lactotrophs → stalk effect hyperprolactinaemia ^[2]

Classification

Category	Size	Clinical Relevance
Microadenoma	< 10 mm	Better surgical cure rates (80–90%) ^[3]
Macroadenoma	≥ 10 mm	More likely to have mass effect, lower surgical cure rate ( < 50%) ^[3]
Giant adenoma	≥ 40 mm	Often invasive into cavernous sinus; very difficult to cure surgically

Pure GH-secreting (most common subtype)
Mixed GH–PRL secreting (mammosomatotroph or mixed adenoma; ~30%)
GH-secreting + TSH, ACTH (very rare)
Plurihormonal (e.g. Pit-1 lineage tumours)

Grade 0–4 based on degree of cavernous sinus involvement on MRI (coronal view). Grade 3–4 = significant cavernous sinus invasion → less likely to achieve surgical cure.

Pituitary adenomas are now termed pituitary neuroendocrine tumours (PitNETs) in the 2022 WHO classification. GH-secreting PitNETs are subcategorised by:

Densely granulated somatotroph tumour — better response to somatostatin analogues
Sparsely granulated somatotroph tumour — more aggressive, less responsive to SSA

Clinical Features

Clinical Features of Acromegaly (SAQ!) — Must Know

The clinical features of acromegaly are insidious in onset (developing over years) ^[1]^[2]^[3]. The average delay from symptom onset to diagnosis is 7–10 years. Features are due to:

GH/IGF-1 excess → soft tissue, bone, and organ overgrowth + metabolic derangement
Local mass effect from the pituitary adenoma
Hypopituitarism from compression of normal pituitary tissue
Hyperprolactinaemia from stalk effect or co-secretion

6.1 Symptoms (with Pathophysiological Basis)

Symptom	Pathophysiological Basis
Enlarging hands and feet (increasing ring size, shoe size)	IGF-1 → periosteal new bone formation (appositional growth) + soft tissue/cartilage hypertrophy. Because epiphyses are fused in adults, bones cannot grow longer — they grow wider ^[1]^[2]
Coarsening of facial features (patients notice gradual change in old photos)	Same mechanism: bony overgrowth of frontal bone (frontal bossing), supraorbital ridges, zygomatic arches; soft tissue thickening of nose, lips, ears
Jaw protrusion (prognathism) → difficulty with dentures, malocclusion, teeth spread apart	Mandibular overgrowth by IGF-1–stimulated periosteal bone deposition; interdental spacing and open bite ^[5]
Headache	Stretching of the dura by the adenoma (dura is richly innervated) AND direct effects of GH excess (even with microadenomas that don't cause mass effect, patients report headache — possibly mediated by raised somatostatin or direct GH/IGF-1 effect on pain pathways)
Deepening of voice	Laryngeal cartilage and vocal cord thickening + submucosal oedema → lower pitch, deep and hollow-sounding voice ^[2]^[3]
Snoring / witnessed apnoeas — obstructive sleep apnoea (OSA) (~50%)	Macroglossia and mucosal hypertrophy of the oropharyngeal tissues → upper airway narrowing → obstruction during sleep ^[5]^[6]. Also, soft tissue thickening of the pharyngeal walls. Central sleep apnoea can also occur (altered central respiratory drive by GH).
Excessive sweating (hyperhidrosis) (> 80%)	GH/IGF-1 stimulates sweat gland hypertrophy and increased activity. Hyperhidrosis is a sign of active acromegaly and one of the most bothersome symptoms; it correlates well with disease activity ^[1]^[2]
Paraesthesiae / numbness in hands — carpal tunnel syndrome (CTS)	IGF-1 → soft tissue and synovial swelling around the carpal tunnel → median nerve compression ^[1]^[2]
Joint pain / stiffness — bilateral knee OA, back pain	Hypertrophic arthropathy due to enlargement of synovial tissue and cartilage → irregular joint surfaces → secondary osteoarthritis. GH also promotes proteoglycan deposition → cartilage thickening initially, but eventually degenerates ^[2]^[3]
Fatigue / lethargy	Multifactorial: sleep apnoea, hypopituitarism (especially adrenal insufficiency, hypothyroidism), depression
Polyuria / polydipsia	Secondary insulin resistance → IGT/DM in up to 20–40% of patients. GH is a counter-regulatory hormone to insulin: ↑hepatic gluconeogenesis, ↑lipolysis → ↑free fatty acids → ↓peripheral glucose uptake ^[1]
Galactorrhoea / menstrual irregularity (women)	Hyperprolactinaemia — either from co-secretion or stalk effect ^[2]
Decreased libido / erectile dysfunction (men)	Hypogonadism from tumour compression of gonadotrophs or hyperprolactinaemia
Visual disturbance — bumping into objects on the side	Suprasellar extension compressing the optic chiasm → bitemporal hemianopia (loss of temporal visual fields bilaterally). This is the classic visual field defect. The lecture title itself hints at this: "I keep on bumping into people on my side" ^[6]^[7]

Symptom	Mechanism
Headache	Dural stretching, raised intrasellar pressure
Visual field defects	Optic chiasm compression (bitemporal hemianopia)
Diplopia	Lateral cavernous sinus invasion → CN III/IV/VI palsy
Hypopituitarism symptoms	Compression of normal pituitary → progressive loss of hormonal axes (typically GH lost first, then LH/FSH, TSH, ACTH — but in the context of a GH-secreting adenoma, GH is paradoxically elevated; other axes may be lost)

6.2 Signs (with Pathophysiological Basis)

The signs of acromegaly are usually striking once you know what to look for. In clinical examinations, you may be asked to examine the hands and then the face.

Sign	Pathophysiological Basis
Glabellar protrusion and increased face height	Frontal bossing — periosteal new bone deposition on the frontal bone, driven by IGF-1 ^[5]
Prominent supraorbital ridges	Same mechanism: bony overgrowth of the orbital rim
Large nose	Cartilage and soft tissue hypertrophy
Mandibular prognathism (protrusion of lower jaw)	Mandibular periosteal bone growth → jaw juts forward; extension of lower jaw ^[5]
Interdental spacing and open bite	Mandibular growth causes teeth to spread apart; malocclusion ^[5]
Enlarged pulp chambers (taurodontism) and root hypercementosis	GH/IGF-1 effects on dental tissues ^[5]
Facial skin and lips thickening	Owing to collagen and glycosaminoglycan (GAG) deposition in the dermis ^[5]
Macroglossia	Soft tissue hypertrophy of the tongue; also mucosal hypertrophy of the oropharyngeal tissues → contributes to OSA ^[5]
Coarse, oily skin	Sebaceous gland hypertrophy (GH/IGF-1 effect)

Acromegalic Facies — Must Recognise

Take effort to remember the facial features of acromegaly ^[5]. In an OSCE or photo station, you should be able to spot: prominent supraorbital ridges, large nose, prognathism, thick lips, interdental spacing, macroglossia, and coarse skin. Compare old and new photos of the patient — the gradual change is often dramatic.

Sign	Pathophysiological Basis
Large hands with broad palms (the handshake feels like gripping a spade)	Periosteal new bone deposition + soft tissue overgrowth
Spatulate fingers ("spade-like hands")	Widened tufts of the distal phalanges + soft tissue thickening
Sweaty palms	Hyperhidrosis from sweat gland hypertrophy — sign of active acromegaly ^[1]^[2]
Thickened, doughy skin	GAG and collagen deposition
Positive Tinel's / Phalen's sign (CTS)	Median nerve compression at the carpal tunnel due to soft tissue and synovial swelling

Sign	Basis
Large feet with thick heel pads	Periosteal bone deposition + soft tissue. May manifest as increasing shoe sizes ^[2]^[3]
Heel pad thickness > 21 mm (lateral X-ray)	Quantitative radiological sign

Sign	Basis
Skin thickening	Collagen and GAG deposition
Hyperhidrosis (> 80%)	Sweat gland hypertrophy — marker of active disease ^[1]
Hirsutism (~56%)	GH/androgen synergy on hair follicles
Skin tags (molluscum fibrosum)	Soft tissue overgrowth; also associated with ↑ risk of colonic polyps
Acanthosis nigricans	Secondary to insulin resistance (hyperinsulinaemia → keratinocyte/fibroblast proliferation via IGF-1 receptor) ^[1]

Sign	Basis
Bilateral knee OA	Hypertrophic arthropathy — cartilage overgrowth then degeneration; weight-bearing joints most affected ^[6]
Kyphosis	Vertebral body overgrowth + disc degeneration
Proximal myopathy (less common)	GH excess causes structural myopathic changes
Pseudogout	GH/IGF-1 promotes calcium pyrophosphate deposition in cartilage ^[2]

Sign	Basis
Hypertension (40%)	GH promotes renal sodium retention (via direct tubular effect) + ↑ peripheral vascular resistance + cardiac remodelling. HTN is a sign of active acromegaly ^[1]^[2]
Cardiomegaly / LVH	Direct GH/IGF-1 effect on cardiomyocyte hypertrophy → concentric LVH → eventual diastolic dysfunction
Signs of heart failure (late)	"Acromegalic cardiomyopathy" — initially diastolic HF, then systolic HF if untreated

Sign	Basis
Goitre (diffuse or multinodular)	IGF-1 stimulates thyroid follicular cell proliferation → often non-toxic but can be toxic ^[2]^[3]
Hepatosplenomegaly	Organomegaly from GH/IGF-1–driven visceral growth ^[1]
Testiculomegaly (in men)	GH-driven gonadal tissue hypertrophy ^[2]

Sign	Basis
Bitemporal hemianopia	Optic chiasm compression by suprasellar tumour extension — the nasal (crossing) fibres at the chiasm are compressed → loss of temporal fields bilaterally ^[6]^[7]
CN III/IV/VI palsy → diplopia	Lateral cavernous sinus invasion ^[2]

If the adenoma compresses normal pituitary tissue sufficiently, you may find:

Secondary hypothyroidism: dry skin, bradycardia, delayed relaxation of reflexes
Secondary adrenal insufficiency: postural hypotension, fatigue (no hyperpigmentation — unlike primary, because ACTH is low, not high)
Hypogonadism: loss of secondary sexual characteristics, testicular atrophy, amenorrhoea

These are complications but they are often the presenting features and thus part of the clinical picture:

Feature	Mechanism
Impaired glucose tolerance (40%) / Type 2 DM (20%)	GH is a counter-regulatory hormone → secondary insulin resistance: ↑ hepatic gluconeogenesis, ↑ lipolysis, ↓ peripheral glucose uptake ^[1]^[2]
Hyperlipidaemia	↑ lipolysis, insulin resistance → dyslipidaemia
Hypercalcaemia / ↑ phosphate	GH → ↑ 1,25-dihydroxyvitamin D synthesis in kidney → ↑ intestinal calcium absorption. Also ↑ renal tubular phosphate reabsorption ^[2]
Renal stones (hypercalciuria)	↑ calcium filtered and excreted

Acromegaly and Colorectal Cancer Risk

Acromegaly is an endocrine risk factor for colorectal cancer — IGF-1 acts as a growth factor for colonic mucosal cells → increased risk of colonic polyps, diverticulosis, and colorectal carcinoma ^[1]^[8]. This is why colonoscopy is recommended at diagnosis and as part of ongoing surveillance.

Some features indicate active, ongoing GH/IGF-1 excess (and may improve with treatment), while bony changes are irreversible:

Active Acromegaly Signs (*)	Irreversible Changes
Hyperhidrosis (> 80%)	Bony overgrowth (prognathism, enlarged hands/feet)
Skin tags	Arthropathy (joint damage)
Hypertension
IGT / DM
Soft tissue swelling
Skin oiliness, CTS

High Yield Summary

Definition: Acromegaly = GH excess in adults (post-epiphyseal fusion); Gigantism = GH excess in children.

Aetiology: GH-secreting pituitary adenoma > 95%. Rare: GHRH-secreting hypothalamic tumours, ectopic GH/GHRH from neuroendocrine tumours.

Associations: MEN-1, Carney complex (cardiac myxoma + spotted pigmentation), McCune-Albright (precocious puberty + café-au-lait + fibrous dysplasia).

Key Clinical Features (SAQ!):

Mass effect: headache, bitemporal hemianopia, CN palsies, hypopituitarism
Soft tissue: coarse facies, prognathism, macroglossia, thick skin/lips (collagen + GAG deposition), deepening voice, CTS, OSA (~50%)
Acral: large hands (spade-like, spatulate fingers), large feet (thick heel pads), ↑ring/shoe size
Skin: hyperhidrosis (> 80%) = active disease marker, hirsutism, skin tags, acanthosis nigricans
MSK: OA (especially knees), hypertrophic arthropathy, pseudogout
CVS: HTN (40%), LVH, cardiomyopathy, diastolic HF → main cause of excess mortality
Metabolic: IGT (40%), DM (20%), ↑lipids, ↑Ca, ↑PO₄, renal stones
Organomegaly: goitre, hepatosplenomegaly, ↑risk of CRC (colonoscopy needed)
Hyperprolactinaemia (~30%): galactorrhoea, menstrual irregularity

Screening: IGF-1 (not random GH — too variable, short half-life).

Gold standard diagnosis: OGTT with GH levels — GH fails to suppress (nadir > 0.4–1 ng/mL) or paradoxical increase (30%).

Imaging: Pituitary MRI. Also full pituitary hormone profile and colonoscopy.

Active Recall - Acromegaly (Definition, Epidemiology, Aetiology, Clinical Features)

When you encounter a patient with features suggestive of acromegaly, you need to think systematically. The differential diagnosis operates on two levels:

What else could mimic the clinical picture of acromegaly? (i.e., a patient with coarse features, large hands, sweating, etc. — is it really acromegaly, or something else?)
If biochemistry confirms GH/IGF-1 excess, what is the underlying cause? (i.e., the aetiological differential of confirmed acromegaly itself)

Let's address both systematically.

Before you even get to the biochemistry, the clinical presentation of acromegaly — coarse facies, large hands, sweating, skin thickening, arthropathy — can overlap with several other conditions. The key question is: does the patient truly have GH/IGF-1 excess, or is something else causing these features?

Condition	Why It Can Mimic Acromegaly	How to Differentiate
Severe primary hypothyroidism (myxoedema)	Facial puffiness, coarse features, macroglossia, thickened skin, deepened voice, CTS — all overlap with acromegaly. Why? Hypothyroidism → ↑ GAG deposition in dermis (myxoedema) → facial/skin swelling; also ↓ metabolic rate → weight gain, lethargy	Check TSH and fT4. In hypothyroidism TSH is elevated, fT4 is low. IGF-1 will be normal or low (GH secretion may actually be reduced). Hypothyroidism features are diffuse puffiness, not bony overgrowth
Pachydermoperiostosis (primary hypertrophic osteoarthropathy)	Thickened skin (pachydermia), digital clubbing, periosteal new bone formation → enlarged hands/feet. The name says it: "pachy" = thick, "dermo" = skin, "periostosis" = periosteal bone growth	Autosomal recessive (HPGD gene); onset in adolescence. No biochemical GH/IGF-1 excess. Key distinguishing feature: pronounced digital clubbing, which is not a feature of acromegaly
Cushing's syndrome	Moon face, truncal obesity, striae ^[9] — facial rounding can look like facial coarsening to the untrained eye. Also: hypertension, diabetes, skin changes overlap	The facial change in Cushing's is fat redistribution (round, plethoric face) rather than bony/soft tissue overgrowth. Look for purple striae, proximal myopathy, easy bruising, thin skin (opposite of acromegaly's thick skin). Biochemistry: 9am morning cortisol → followed up by suppression tests ^[10]
Paget's disease of bone	Skull enlargement (increasing hat size), bony deformities → can be confused with acromegalic bony changes	Paget's is focal (often skull, pelvis, long bones), not generalised. Markedly elevated alkaline phosphatase. Normal IGF-1
Familial/constitutional large stature	Large hands, tall stature — can raise the question of acromegaly or gigantism	No progressive coarsening of features, no sweating, no metabolic complications. Normal IGF-1
Marfan syndrome / Homocystinuria	Tall stature, long extremities (but arachnodactyly, not spade-like hands)	Marfanoid habitus is tall and thin with long slender fingers — opposite of acromegalic broad, thick hands. Lens subluxation, aortic root dilatation
Insulin resistance syndromes (severe)	Acanthosis nigricans, skin tags — overlap with acromegaly's insulin resistance features	Check IGF-1. In pure insulin resistance without GH excess, IGF-1 is normal
Medications: minoxidil, phenytoin, cyclosporin	Can cause coarse facial features, gingival hyperplasia, hirsutism	Drug history is key. No biochemical GH/IGF-1 excess

Physical Exam Clue: Acromegalic vs. Cushing Facies

In the endocrine data interpretation session, the teaching point is to look for acromegalic / Cushing facies during physical examination of a patient with secondary hypertension ^[10]. Remember:

Acromegaly → bony overgrowth + soft tissue thickening (prognathism, supraorbital ridges, thick skin)
Cushing's → fat redistribution (moon face, plethora, buffalo hump, thin skin, striae) These are fundamentally different processes even though both produce a "changed face."

2. Aetiological Differential Diagnosis of Confirmed GH/IGF-1 Excess

Once you have confirmed that the patient has elevated IGF-1 and non-suppressible GH on OGTT, the next question is: why does this patient have excess GH?

Category	Specific Cause	Frequency	Key Features
Pituitary (most common)	GH-secreting pituitary adenoma (somatotroph adenoma)	> 95% ^[1]^[2]	Sporadic in most cases. May be micro ( < 1 cm) or macroadenoma ( > 1 cm). ~70% are macroadenomas at diagnosis. ~30% co-secrete prolactin ^[2]. Can be part of MEN-1, Carney complex, McCune-Albright, or FIPA
	Mixed GH–PRL secreting adenoma (mammosomatotroph)	Subset of above	Higher PRL levels; consider MEN-1 if multiple pituitary adenomas
Hypothalamic	GHRH-secreting hypothalamic tumour (gangliocytoma / ganglioneuroma / hamartoma)	Rare	Excess GHRH → somatotroph hyperplasia (not adenoma). Pituitary on MRI may show diffuse enlargement rather than a discrete adenoma ^[1]^[11]
Ectopic GHRH secretion	Peripheral neuroendocrine tumours secreting GHRH	Rare	Pancreatic islet-cell tumours, small cell lung cancer, medullary thyroid carcinoma, pheochromocytoma, adrenal adenoma, bronchial carcinoid ^[11]. Again causes somatotroph hyperplasia. Plasma GHRH levels are markedly elevated
Ectopic GH secretion	Pancreatic islet-cell tumours, lymphoma	Very rare	Direct GH production by the tumour. Extremely uncommon ^[11]

High Yield — Aetiological DDx of Acromegaly (SAQ!)

GH-secreting pituitary adenoma accounts for > 95% of cases ^[1]^[2]^[11]. The rare causes to remember are:

GHRH-secreting hypothalamic ganglioneuroma
Ectopic GHRH secretion by neuroendocrine tumours (bronchial/pancreatic carcinoid, SCLC, MTC, phaeochromocytoma)
Ectopic GH secretion (pancreatic islet-cell tumour, lymphoma) ^[11]

The distinction matters because ectopic GHRH causes somatotroph hyperplasia (not adenoma) → pituitary surgery alone will not cure the patient; you need to find and treat the ectopic source.

Feature	Pituitary Adenoma	Ectopic GHRH	Ectopic GH
Frequency	> 95%	Rare	Very rare
Pituitary MRI	Discrete adenoma	Diffuse pituitary enlargement (hyperplasia) or normal	Normal pituitary
Plasma GHRH	Low/normal	Markedly elevated ( > 300 pg/mL)	Low/normal
Serum GH	Elevated	Elevated	Elevated
Serum IGF-1	Elevated	Elevated	Elevated
OGTT GH suppression	Non-suppressible	Non-suppressible	Non-suppressible
Other clues	Visual field defects, hypopituitarism	Symptoms of primary tumour (e.g. lung mass, abdominal mass)	Very rare; usually known malignancy

If MRI does not show a clear pituitary adenoma in a biochemically confirmed acromegaly patient, always measure plasma GHRH to exclude an ectopic source ^[2]^[11].

3. Differential Diagnosis by Presenting Feature

Acromegaly is insidious and patients often present with one or two dominant complaints rather than the full syndrome. A practical approach is to consider what other conditions might explain the presenting complaint:

Acromegaly is one of the endocrine causes of secondary hypertension ^[10]. The full differential for endocrine secondary hypertension includes:

Cause	Screening Test
Acromegaly	IGF-1 levels ^[10]
Conn syndrome (primary aldosteronism) / bilateral adrenal hyperplasia	Aldosterone-renin ratio (ARR)
Cushing's syndrome	9am morning cortisol → followed up by suppression tests ^[10]
Pheochromocytoma	Plasma/24h urine metanephrines
Obesity (most common cause of secondary HT)	Clinical + metabolic workup
OSA	Polysomnography ^[10]
Renovascular causes (renal artery stenosis)	Ultrasound + Doppler ^[10]
Coarctation of aorta	BP differential between arms and legs, echocardiography
Thyrotoxicosis	TSH, fT4
Drug-induced (glucocorticoids, cocaine, NSAIDs)	Drug history

GC Lecture — Secondary Hypertension Workup

From the Endocrine Data Interpretation session ^[10]: When evaluating a young patient with hypertension, the signs to look for in physical exam include acromegalic / Cushing facies plus a systems review. Finish off with urine dipstick. Targeted investigations for different differentials:

Cushing's → 9am morning cortisol → suppression tests
Acromegaly → IGF-1 levels
Obesity / OSA → Polysomnography
Renovascular causes → Ultrasound + Doppler

Acromegaly is a secondary cause of CTS ^[12]. The differential for CTS includes:

Cause	Category
Primary (most common)	Ageing, female sex
Endocrine	DM, hypothyroidism, acromegaly ^[12]
Inflammatory	RA, gout
SOL	Ganglion cyst
Post-traumatic	Wrist fracture (Colles')
Physiological	Obesity, pregnancy

Why does acromegaly cause CTS? IGF-1 → soft tissue and synovial hypertrophy around the carpal tunnel → compression of the median nerve within the rigid osseofibrous tunnel.

Acromegaly is listed as an endocrinopathy causing secondary DM ^[9]^[13]. The full differential of endocrine causes of DM:

Endocrinopathy	Mechanism of Hyperglycaemia
Acromegaly	GH is a counter-regulatory hormone → ↑ hepatic gluconeogenesis, ↑ lipolysis, ↓ peripheral glucose uptake → insulin resistance
Cushing's syndrome	Cortisol → ↑ gluconeogenesis, ↑ insulin resistance
Pheochromocytoma	Catecholamines → ↑ glycogenolysis, ↑ gluconeogenesis, ↓ insulin secretion
Glucagonoma	Glucagon excess → ↑ hepatic glucose output
Somatostatinoma	Somatostatin inhibits insulin secretion
Hypothyroidism	↓ insulin clearance, altered glucose metabolism
Thyrotoxicosis	↑ glucose absorption, ↑ glycogenolysis

OSA occurs in ~50% of acromegaly patients ^[2]^[3]. The differential for OSA also includes: obesity (by far the most common cause), hypothyroidism (myxoedema → pharyngeal tissue swelling), tonsillar hypertrophy, structural craniofacial abnormalities, neuromuscular disorders. In acromegaly, OSA results from macroglossia and mucosal hypertrophy of the oropharyngeal tissues ^[5].

Acromegalic arthropathy can mimic degenerative OA but tends to affect weight-bearing joints (knees, hips, spine) at a younger age than expected. Also consider pseudogout (CPPD) which acromegaly predisposes to ^[2].

If the clinical scenario starts with the imaging finding of a pituitary mass, the differential of what that mass could be secreting (or not) is important:

Adenoma Type	Hormone Secreted	Key Clinical Features
Prolactinoma (most common functioning adenoma)	Prolactin	Galactorrhoea, amenorrhoea, hypogonadism. First-line Rx: dopamine agonist
GH-secreting adenoma	GH (± PRL in ~30%)	Acromegaly / gigantism ^[1]^[2]
ACTH-secreting adenoma (Cushing's disease)	ACTH	Cushing's features: moon face, truncal obesity, striae, proximal myopathy ^[14]
TSH-secreting adenoma (thyrotropinoma)	TSH	Hyperthyroidism with non-suppressed TSH (secondary hyperthyroidism). Thyroid scan: diffuse uptake ^[15]
Gonadotroph adenoma	FSH/LH (often non-functional)	Usually clinically silent; presents with mass effect
Non-functioning pituitary adenoma	None	Mass effect only: headache, bitemporal hemianopia, hypopituitarism
Craniopharyngioma	None	Calcified suprasellar mass; children/young adults; visual field defects, DI, growth failure
Rathke's cleft cyst	None	Incidental finding or mild mass effect
Pituitary metastasis	None (or panhypopituitarism)	Breast, lung most common primaries. Posterior pituitary affected first (systemic blood supply) → DI as early feature ^[4]
Pituitary apoplexy	Sudden loss of function	Haemorrhagic infarction of an adenoma → sudden severe headache, CN III palsy, hypopituitarism. Neurosurgical emergency ^[16]

Clinical Scenario	DDx to Consider Alongside Acromegaly	Key Distinguishing Investigation
Coarse facies	Hypothyroidism, Paget's, pachydermoperiostosis, familial	IGF-1, TSH, ALP
Young hypertension	Conn's, Cushing's, phaeochromocytoma, renal artery stenosis, coarctation, obesity, OSA ^[10]	IGF-1, ARR, cortisol, metanephrines, renal US Doppler ^[10]
CTS (bilateral)	DM, hypothyroidism, RA, pregnancy ^[12]	IGF-1, TSH, RF/anti-CCP, βhCG
New-onset DM + unusual features	Cushing's, phaeochromocytoma, glucagonoma ^[13]	IGF-1, cortisol, metanephrines
OSA in non-obese patient	Hypothyroidism, acromegaly, structural airway abnormality	IGF-1, TSH
Pituitary mass on MRI	Prolactinoma, non-functioning adenoma, Cushing's disease, TSHoma, craniopharyngioma, metastasis	Full pituitary profile: PRL, IGF-1, cortisol, TSH/fT4, FSH/LH, testosterone/oestradiol

High Yield Summary — Differential Diagnosis of Acromegaly

Clinical mimics: Hypothyroidism (puffiness, macroglossia, CTS), Cushing's syndrome (facial change, HTN, DM), pachydermoperiostosis, Paget's disease of bone.

Aetiological DDx of confirmed GH excess:

GH-secreting pituitary adenoma > 95%
Ectopic GHRH (neuroendocrine tumours — bronchial/pancreatic carcinoid, SCLC, MTC, phaeochromocytoma)
Hypothalamic GHRH-secreting ganglioneuroma
Ectopic GH (pancreatic islet-cell tumour, lymphoma) — very rare

Key distinguishing point: If MRI shows no discrete adenoma, measure plasma GHRH to exclude ectopic source. Ectopic GHRH causes somatotroph hyperplasia, not adenoma.

Acromegaly as a DDx of other presentations: Secondary hypertension, CTS, secondary DM, OSA in non-obese patient, premature OA.

Endocrine causes of secondary hypertension (high-yield exam list): Acromegaly, Conn syndrome, Cushing's syndrome, pheochromocytoma ^[10].

Active Recall - Differential Diagnosis of Acromegaly

^[1] Senior notes: Maksim Medicine Notes.pdf (Endocrinology — Acromegaly section, p108) ^[2] Senior notes: Ryan Ho Endocrine.pdf (Section 5.2.3 Acromegaly, p111) ^[3] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.8.4.3 Acromegaly, p444) ^[4] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (pituitary blood supply discussion) ^[5] Senior notes: Block A - Introduction to Endocrine investigations.pdf (facial features, OSA mechanism, p8) ^[9] Senior notes: Block A - Polyuria and polydipsia_ glucose metabolism; diabetes mellitus; diabetic ketoacidosis.pdf (endocrinopathies causing DM, p8) ^[10] Senior notes: Block A - Endocrine Data Interpretation.pdf (secondary hypertension DDx and investigations, p4) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Aetiology of acromegaly, p1613) ^[12] Senior notes: Maksim Surgery Notes.pdf (CTS risk factors — acromegaly, p245) ^[13] Senior notes: Adrian Lui Pediatrics Notes.pdf (Endocrinopathies causing DM, p293) ^[14] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours.pdf (Cushing's features, p14) ^[15] Senior notes: Block A - I am losing weight and sweating all the time.pdf (TSH-secreting pituitary adenoma thyroid scan, p14) ^[16] Senior notes: Ryan Ho Neurology.pdf (Pituitary apoplexy, p166)

Before diving into specific tests, recall the general sequence of endocrine investigations taught in the introductory endocrine investigations lecture ^[17]:

When working up any suspicion of hormonal excess or deficiency, the steps in order are:

History and PE

Baseline blood tests → CBC / LRFT

Screening blood biochemistry tests

Confirmatory tests (sometimes dynamic suppression/stimulation tests) → also workup for complications

Imaging with MRI / CT

Invasive tests (venous sampling)

General principle: less invasive before more invasive ^[17]

Endocrine Axiom: Biochemistry BEFORE Imaging

Endocrine is unique in that you need biochemistry before imaging — resolution is too high with our imaging nowadays → we might find benign lesions (incidentalomas) which are not related to the condition ^[17]. Always confirm biochemical excess/deficiency first, THEN image to localise the source. This principle applies directly to acromegaly: get IGF-1 and OGTT before rushing to MRI.

Another fundamental principle: many hormones are released in a diurnal rhythm → it is crucial to know when to take blood ^[17]. This is precisely why random GH is useless — GH is pulsatile and affected by sleep, stress, and exercise. Instead, we use IGF-1 (stable integrated marker) and OGTT (standardised dynamic test).

For acromegaly specifically, the logic of investigation is:

Suspicion of excess → use a suppression test (OGTT) to see if the hormone axis can be appropriately suppressed. If it cannot be suppressed, the axis is autonomous.
This is the mirror image of suspected deficiency, where you would use a stimulation test (e.g. synacthen test for cortisol deficiency, insulin tolerance test for GH deficiency).

2. Diagnostic Criteria for Acromegaly

There is no single "diagnostic criterion" as in rheumatological diseases; instead, the diagnosis of acromegaly relies on a stepwise biochemical approach endorsed by international consensus (Endocrine Society 2014, updated Pituitary Society 2021):

Parameter	Detail
Test	Serum IGF-1 (Insulin-like Growth Factor-1)
Why IGF-1 and not random GH?	GH is not useful for screening: diurnal rhythm, influenced by exercise and stress, short half-life (~15–20 min) ^[1]^[6]. Random GH is highly variable depending on personal status and does not indicate much if interpreted by itself ^[4]. In contrast, IGF-1 has a long half-life (~18–20 hours), is relatively stable throughout the day, and reflects the integrated 24-hour GH secretion
Interpretation	Compared to age- and sex-matched reference range (IGF-1 physiologically declines with age; physiologically high in puberty) ^[2]^[3]. An elevated IGF-1 for age is highly suggestive of GH excess
Caveats	IGF-1 can be falsely low in: liver failure (↓ hepatic synthesis), malnutrition, poorly controlled DM, hypothyroidism, oestrogen use. IGF-1 can be falsely high in: adolescence, pregnancy. Always interpret in clinical context

For acromegaly screening: IGF-1 levels ^[10]

This is the gold standard confirmatory test for acromegaly ^[1]^[2]^[3]^[6]^[18].

Parameter	Detail
Indication	Done when IGF-1 is elevated, or in equivocal cases (equivocal IGF-1, no typical manifestations) ^[2]
Principle	In normal physiology, oral glucose → ↑ insulin → suppresses GH secretion. In acromegaly, the autonomous GH secretion from the adenoma is not suppressible by glucose
Protocol	75g anhydrous glucose in 200–250 mL water, drunk over 3–5 min ^[18]. Serial GH measurements at baseline, 30, 60, 90, and 120 minutes (the "extended OGTT" — distinct from the standard 2-point OGTT used for DM)
Normal response	GH suppresses to < 1 ng/mL (by older assay) or < 0.4 ng/mL (by ultrasensitive assay) after 2 hours ^[2]^[3]
Acromegaly	GH fails to suppress — nadir remains > 0.4 ng/mL (AACE 2011) or > 1 ng/mL (AES 2014) ^[2]^[3]. In ~30% of cases, there is a paradoxical increase in GH after glucose load ^[2]^[3]
Why paradoxical increase?	Some GH-secreting adenomas aberrantly express receptors (e.g. GIP receptor, TRH receptor) that respond paradoxically to glucose or its downstream signals — this is a hallmark of tumour autonomy

OGTT in Acromegaly — Procedures and Precautions (High Yield)

From the Chemical Pathology notes ^[18], the procedures for OGTT include:

No carbohydrate restriction for ≥ 3 days prior to test (daily CHO > 150g)
10–14 hour fasting with water ad lib
Smoking and physical exercise not allowed on the morning of the test
75g anhydrous glucose in 200–250 mL water to be drunk over 3–5 min

Contraindications: C/I in patients under stress (post-surgery, trauma, sepsis, extreme psychological stress) — prone to false positive (stress ↑ GH). C/I in patients with periodic hypokalaemic paralysis (OGTT can trigger attacks of hypoK paralysis) ^[18]. Some individuals may have vasovagal symptoms → nursing supervision preferred ^[18].

For acromegaly diagnosis, the OGTT uses serial GH measurements (not just the 2-hour glucose value as in DM diagnosis), though glucose values are also recorded (may reveal concurrent IGT/DM).

Criterion	Interpretation
Elevated serum IGF-1 (age- and sex-adjusted)	Screening positive
GH nadir > 1 ng/mL (or > 0.4 ng/mL by ultrasensitive assay) during 75g OGTT	Confirmed acromegaly
Paradoxical GH rise during OGTT	Strongly supports diagnosis (~30% of cases)
Concordant clinical features	Supports but alone insufficient — always need biochemical confirmation

Current practice (2024–2026 Pituitary Society consensus): The recommended cut-off for the GH nadir is < 0.4 ng/mL using modern immunometric assays calibrated to WHO IS 98/574. If the GH nadir is between 0.4–1.0 ng/mL with an elevated IGF-1 and typical clinical features, the diagnosis is still made. If IGF-1 is clearly elevated with typical features, some centres may forgo OGTT altogether and proceed directly to imaging.

4. Investigation Modalities — Detailed Breakdown

4.1 Biochemical Investigations

Aspect	Detail
Role	Screening test of choice ^[1]^[2]^[10]
Mechanism	GH stimulates hepatic IGF-1 production. IGF-1 circulates bound to IGF-binding proteins (especially IGFBP-3) and reflects mean 24-hour GH secretion
Sample	Fasting not strictly required (IGF-1 is relatively stable), but ideally a morning sample. No special preparation needed
Reference range	Must be age- and sex-adjusted ^[2]. IGF-1 is highest during puberty and declines with age. Using adult-only ranges for an adolescent would be misleading
Sensitivity	Very high (> 95%) when using age-adjusted ranges
Specificity	Moderate — can be elevated in pregnancy, adolescence; can be low in liver disease, malnutrition
Follow-up role	Used for monitoring disease activity after treatment. Target: normalisation of IGF-1 to age-adjusted range

Aspect	Detail
Role	NOT useful for diagnosis ^[1]^[4]
Why?	Diurnal rhythm, pulsatile secretion, influenced by exercise and stress, short half-life ^[1]. A single value could be anywhere from undetectable to > 20 ng/mL in a normal person depending on timing
One exception	A GH level < 0.4 ng/mL with normal IGF-1 effectively rules out acromegaly. But an elevated random GH alone is not diagnostic
In confirmed acromegaly	Random GH can be used alongside IGF-1 for monitoring post-treatment disease activity

Why Not Random GH? (Must Understand)

GH not useful: diurnal rhythm, influenced by exercise and stress, short half-life ^[1]. Random GH is highly variable on personal status, does not indicate a lot if interpreted by itself ^[4]. This is a fundamental concept that examiners love to test — never use random GH alone to diagnose or exclude acromegaly.

Aspect	Detail
Role	Gold standard confirmatory test ^[1]^[2]^[3]^[18]
Protocol	75g glucose load. Serial GH drawn at 0, 30, 60, 90, 120 min. Also measures glucose at 0 and 120 min (can simultaneously diagnose DM/IGT)
Preparation	≥ 3 days of unrestricted carbohydrate intake ( > 150g/day); 10–14 hour fast; no smoking or exercise on morning of test ^[18]
Normal result	GH nadir < 0.4 ng/mL (ultrasensitive assay) or < 1 ng/mL (conventional assay) ^[2]^[3]
Acromegaly	Inadequate GH suppression: nadir > 0.4 ng/mL (AACE 2011) or > 1 ng/mL (AES 2014) ^[2]^[3]. ~30% show paradoxical GH increase ^[2]^[3]
Concurrent findings	OGTT also reveals IGT (2h glucose 7.8–11.0 mmol/L) or DM (2h glucose ≥ 11.1 mmol/L) — complication of GH-induced insulin resistance
C/I	Patients under stress (FP), known DM (potentially harmful hyperglycaemia), periodic hypokalaemic paralysis ^[18]
Post-treatment use	OGTT GH nadir is used to confirm biochemical remission after surgery. Remission = GH nadir < 0.4 ng/mL + normal IGF-1

Aspect	Detail
Role	Occasionally used when OGTT is contraindicated or impractical
Method	5 samples taken every 30 min over 2 hours; calculate the mean
Interpretation	Mean GH < 2.5 ng/mL with normal IGF-1 suggests adequate disease control. Less standardised than OGTT

Aspect	Detail
Role	Measure when no discrete adenoma on MRI to exclude ectopic GHRH source ^[2]^[11]
Interpretation	Markedly elevated ( > 300 pg/mL) → ectopic GHRH-secreting tumour (e.g. bronchial/pancreatic carcinoid). Normal/low → favours pituitary origin

This is essential once acromegaly is confirmed, for two reasons: (1) to detect co-secretion of other hormones, and (2) to detect hypopituitarism from tumour compression.

Hormone	Why Test	Expected Findings in Acromegaly
Prolactin	~30% co-secrete PRL ^[2] or stalk effect hyperprolactinaemia	Often mildly-moderately elevated. Very high PRL ( > 200 µg/L) favours co-secretion or prolactinoma
Morning cortisol / ACTH	Assess for secondary adrenal insufficiency from tumour compression of corticotrophs	May be low if significant compression. If abnormal → short synacthen test to confirm
TSH, free T4	Assess for secondary hypothyroidism (low fT4 with inappropriately normal/low TSH)	fT4 may be low if significant compression
LH, FSH	Assess for hypogonadism	May be low (hypogonadotropic hypogonadism from compression)
Testosterone (men) / Oestradiol (premenopausal women)	Gonadal function	Often low due to hypogonadism

For all endocrine investigations, after realising one pituitary axis is abnormal, cannot stop there — have to check the other anterior pituitary hormones as well, a holistic plan to not miss anything ^[4].

4.2 Imaging Investigations

Aspect	Detail
Role	Gold standard imaging modality for localisation once biochemistry confirms acromegaly ^[2]^[3]
Why MRI?	Contrast MRI for pituitary → soft tissue resolution is superior ^[17]. Can delineate microadenomas ( < 10 mm), cavernous sinus invasion (Knosp grade), suprasellar extension, optic chiasm relationship
Protocol	Thin-cut (2–3 mm slices) coronal and sagittal T1-weighted sequences pre- and post-gadolinium, plus T2-weighted sequences. Pre- and post-contrast important for endocrine studies — need to show washout characteristics ^[17]
Typical findings	Microadenoma: hypo-enhancing lesion within the pituitary on post-contrast images (adenoma enhances less than normal pituitary). Macroadenoma: sellar mass with suprasellar extension ± cavernous sinus invasion. ~70% of GH-secreting adenomas are macroadenomas at diagnosis
Knosp classification	Assessed on coronal MRI: Grade 0 (no cavernous sinus involvement) → Grade 4 (total encasement of intracavernous carotid). Grade 3–4 = unlikely complete surgical resection
Additional findings	Look for: compression of optic chiasm, invasion of cavernous sinus, size of residual normal pituitary, pituitary stalk deviation

Imaging Principle — Biochemistry Before MRI

In endocrine, you need biochemistry before imaging ^[17]. Pituitary incidentalomas are found in up to 10–20% of healthy individuals on MRI. Finding a small pituitary lesion without biochemical confirmation of GH excess does NOT make the diagnosis of acromegaly. Conversely, a normal-appearing MRI with unequivocal biochemical GH excess warrants searching for ectopic sources.

Aspect	Detail
Role	Only indicated if ectopic GHRH source suspected (i.e. elevated plasma GHRH with no clear pituitary adenoma)
Looking for	Neuroendocrine tumours: bronchial carcinoid, pancreatic islet-cell tumour, small cell lung cancer, pheochromocytoma ^[11]

Aspect	Detail
Role	Contrast CT for adrenal → fast, good resolution ^[17]. Only if concomitant adrenal pathology suspected (e.g. pheochromocytoma in MEN-1)

Once acromegaly is confirmed, a comprehensive complication workup is needed because the disease is often diagnosed late with established organ damage:

Investigation	Rationale	Expected Findings
Colonoscopy	↑ risk of colon CA, polyps, diverticulosis (IGF-1 acts as growth factor for colonic mucosal cells) ^[1]^[2]^[3]^[8]	Polyps (especially adenomatous), diverticulosis. Baseline colonoscopy at diagnosis; surveillance every 3–5 years depending on findings
OGTT for DM / HbA1c	IGT (40%), T2DM (20%) from GH-induced insulin resistance ^[1]^[2]	Fasting glucose, 2h OGTT glucose, HbA1c. Diagnose concurrent DM/IGT
Echocardiography	LVH, cardiomyopathy with diastolic HF, VHD ^[2]	Concentric LVH, diastolic dysfunction (E/A ratio reversal), valvular abnormalities
ECG	Screen for arrhythmias, LVH	LVH voltage criteria, conduction abnormalities
Blood pressure monitoring	HTN in 40% ^[1]^[2]	Home BP or 24-hour ABPM
Sleep study (polysomnography)	OSA in ~50% ^[2]. For OSA → polysomnography ^[10]	Obstructive apnoeas/hypopnoeas, desaturation index, AHI calculation
Visual field perimetry	Assess optic chiasm compression	Bitemporal hemianopia (classic); may show superior temporal quadrantanopia if chiasm compressed from below
Lipid profile	↑ lipids from insulin resistance and GH excess ^[2]	↑ triglycerides, ↑ LDL, ↓ HDL
Calcium and phosphate	↑ Ca, ↑ PO₄ ^[2]. GH → ↑ 1,25-diOH Vitamin D → ↑ Ca absorption; ↑ renal tubular PO₄ reabsorption	Hypercalcaemia, hyperphosphataemia
Renal function + urine calcium	Renal stones (hypercalciuria) ^[2]	↑ 24h urine calcium
Lateral skull X-ray	Historical/teaching — shows sellar enlargement, thickened skull vault	Enlarged sella turcica, frontal bossing, prognathism. Largely replaced by MRI but may be seen in exams
Hand X-ray	Teaching/historical — shows acral changes	Tufting of distal phalanges, widened joint spaces (early), narrowed joint spaces (late OA), soft tissue thickening
Heel pad thickness (lateral foot X-ray)	> 21 mm in acromegaly	Rarely used now; clinical curiosity

Investigation	When to Consider
Serum calcium + PTH	MEN-1 screen (primary hyperparathyroidism)
Fasting gut hormones (gastrin, VIP, glucagon, insulin)	MEN-1 screen (pancreatic NETs)
Cardiac MRI / Echo	Carney complex (cardiac myxoma)
Genetic testing (MEN1 gene, AIP gene, PRKAR1A gene)	Young patients ( < 30), family history, aggressive adenomas

5. Data Interpretation Pearls

IGF-1 Level	Clinical Interpretation	Next Step
Clearly elevated for age	High probability of GH excess	Proceed to OGTT for confirmation
Borderline / equivocal	Cannot confirm or exclude	Proceed to OGTT — essential
Normal for age	Acromegaly very unlikely	Look for alternative diagnosis. Re-check if strong clinical suspicion (consider factors lowering IGF-1: liver disease, malnutrition)

GH Nadir During OGTT	Interpretation
< 0.4 ng/mL (ultrasensitive assay)	Normal suppression → acromegaly excluded
0.4–1.0 ng/mL	Grey zone — interpret with IGF-1 and clinical picture. If IGF-1 elevated + typical features → still diagnose acromegaly
> 1.0 ng/mL	Definite inadequate suppression → confirmed acromegaly ^[2]^[3]
Paradoxical rise in GH	Pathognomonic for adenoma autonomy (~30%) ^[2]^[3]

Finding	Interpretation
Discrete hypo-enhancing lesion < 10 mm	Microadenoma — good surgical prognosis (80–90% cure) ^[3]
Lesion ≥ 10 mm with suprasellar extension	Macroadenoma — assess optic chiasm compression, Knosp grade
Knosp grade 3–4 (cavernous sinus invasion)	Unlikely to achieve complete surgical resection — multimodal therapy needed
Diffuse pituitary enlargement without discrete adenoma	Think ectopic GHRH → measure plasma GHRH → CT chest/abdomen
Normal pituitary	Very rare — consider occult microadenoma or ectopic GH secretion

Investigation	Purpose	Key Finding
Serum IGF-1	Screening	Elevated for age
75g OGTT with serial GH	Gold standard confirmation	GH nadir > 0.4–1 ng/mL; paradoxical rise in 30%
Pituitary MRI + gadolinium	Localisation	Adenoma (micro or macro); assess chiasm, cavernous sinus
Full pituitary hormone profile	Co-secretion and hypopituitarism	PRL co-secretion ~30%; may have secondary hypothyroidism, adrenal insufficiency, hypogonadism
Plasma GHRH	Exclude ectopic source	Elevated > 300 pg/mL → ectopic GHRH tumour
Visual field perimetry	Mass effect	Bitemporal hemianopia
Colonoscopy	CRC screening	Polyps, diverticulosis
Echocardiography	Cardiac complications	LVH, diastolic dysfunction
OGTT glucose / HbA1c	Metabolic complications	IGT or DM
Sleep study	OSA	AHI elevated

High Yield Summary — Diagnosis of Acromegaly

Diagnostic Approach (in order):

Clinical suspicion → coarse features, large hands/feet, sweating, HTN, OSA, DM, visual field loss
Screen: Serum IGF-1 (not random GH — GH has diurnal rhythm, short half-life, influenced by stress/exercise) ^[1]^[10]
Confirm: 75g OGTT with serial GH — GH nadir > 0.4–1 ng/mL confirms diagnosis; ~30% show paradoxical GH rise ^[2]^[3]
Localise: Pituitary MRI with gadolinium — biochemistry BEFORE imaging ^[17]
If no adenoma on MRI: measure plasma GHRH → exclude ectopic GHRH source ^[2]^[11]
Full workup: pituitary hormone profile (PRL, cortisol, TSH/fT4, FSH/LH), visual fields, colonoscopy, echo, OGTT for DM, sleep study

OGTT Procedure: ≥ 3 days unrestricted CHO, 10–14h fast, no smoking/exercise on test morning, 75g glucose in 200–250 mL water over 3–5 min. C/I in stress, known DM, periodic hypoK paralysis ^[18].

Key principle: In endocrine, biochemistry before imaging — resolution is too high with modern imaging, may find incidentalomas unrelated to the condition ^[17].

Active Recall - Diagnosis and Investigations of Acromegaly

Before discussing specific modalities, understand what we are trying to achieve. Acromegaly is driven by autonomous GH/IGF-1 excess, and the overall mortality is 1.72× that of the general population, mainly due to cardiovascular risk ^[2]. The goals are:

Goal	Target	Why
Biochemical remission	IGF-1 normalised to age-adjusted range + GH nadir < 0.4–1 ng/mL on OGTT (or random GH < 1 ng/mL) ^[1]^[2]^[3]	Normalising GH/IGF-1 reduces excess mortality back towards baseline
Tumour control	Reduction or stabilisation of tumour size	Prevent/relieve mass effect (visual field loss, CN palsies, hypopituitarism)
Symptom relief	Resolution of hyperhidrosis, headache, soft tissue swelling	Improve quality of life; soft tissue changes are partially reversible, bony changes are not
Complication management	Control HTN, DM, OSA, screen for CRC	Address the multi-system damage already present at diagnosis
Preserve pituitary function	Avoid iatrogenic hypopituitarism where possible	Any treatment modality can damage normal pituitary tissue

There are three pillars of treatment, used alone or in combination:

Surgery (first-line for most patients)
Medical therapy (second-line, or adjunctive)
Radiotherapy (third-line, when surgery + medical therapy fail)

The management is sequential and stepwise — not all modalities are needed in every patient.

4.1 Transsphenoidal Surgery (TSS)

Transsphenoidal hypophysectomy is the first-line treatment for acromegaly ^[1]^[3]^[19].

The name tells you the route: "trans" = through, "sphenoidal" = the sphenoid bone/sinus. The surgeon accesses the pituitary via the nose → sphenoid sinus → floor of the sella turcica, avoiding craniotomy entirely.

Aspect	Detail
Approach	Transphenoidal → route of choice ^[19]. Two sub-approaches: transnasal endoscopic (now preferred — better visualisation, minimally invasive) or sub-labial (incision under upper lip). Modern practice overwhelmingly favours the endoscopic transnasal route
Alternative approach	Transfrontal (transcranial) → for those with very large suprasellar extension, severe chiasmal compression where the transsphenoidal corridor cannot reach the entire tumour ^[19]
Technique	Microscopic vs. endoscopic. Endoscopic TSS has become the standard at most high-volume centres

Indications for Surgery

Indications for surgery for a pituitary tumour ^[19]:

All tumours that are causing pituitary hyperfunction (including GH-secreting adenomas — acromegaly is itself an indication)

All macroadenomas ( > 1 cm in size)

Vision loss / visual field deficits

Mass effect of the lesion (headaches, or causing hypopituitarism)

Pituitary apoplexy (emergency)

In acromegaly specifically:

Microadenoma with no cavernous sinus invasion → excellent cure rate → always offer surgery
Macroadenoma without significant cavernous sinus invasion → surgery as first-line (even if complete resection is unlikely, debulking improves subsequent medical therapy response)
Invasive macroadenoma (Knosp 3–4) → surgery may be offered for debulking, but cure is unlikely; primary medical therapy may be considered instead

Cure Rates

Tumour Type	Surgical Cure Rate
Microadenoma	80–90% ^[3]
Macroadenoma	< 50% ^[3]
Invasive / giant adenoma	< 10–20% (debulking role)

Can repeat surgery if MRI detects residual tumour ^[3]. Second surgery is reasonable if a clear surgical target remains.

Advantages of Surgery [19]

Rapid reduction in GH secretion and tumour size — biochemical normalisation can occur within hours–days
Tissue for histopathological diagnosis (confirms adenoma type, granulation pattern, helps guide further treatment)
Immediate relief of mass effect (decompression of chiasm → visual field improvement, often within days)

Complications of Transsphenoidal Surgery

Complication	Mechanism	Frequency
Iatrogenic hypopituitarism	Damage to normal pituitary during adenoma excision → loss of one or more hormonal axes	5–15% for new deficits
Diabetes insipidus (DI)	Damage to posterior pituitary or pituitary stalk → ↓ ADH (vasopressin) → polyuria, polydipsia. Often transient (days–weeks), occasionally permanent	10–20% transient; 1–5% permanent
CSF rhinorrhoea	Breach of the dural floor during surgery → CSF leaks through the nose. Will require antibiotics to prevent ascending meningitis, as well as decision to go back to OT for repair ^[19]	2–5%
Postoperative bleeding	Haemorrhage into the surgical cavity or from sphenopalatine artery	Rare
Meningitis	Secondary to CSF leak or direct contamination during transnasal approach	< 1%
Vision loss	Inadvertent damage to optic apparatus	Very rare in experienced hands
Residual / recurrence	Especially for macroadenomas ^[19] — incomplete excision. Up to 50% of macroadenomas have persistent disease	Common for large tumours
Vascular injury / CVA	Injury to internal carotid artery (runs within cavernous sinus, lateral to pituitary)	Very rare
ENT symptoms	Nasal crusting, septal perforation, sinusitis	Mild; common transiently
Mortality	Overall perioperative mortality	< 0.5% at experienced centres

Prolactinoma Is the Exception

Despite being hyperfunctional, prolactinomas are preferably treated medically (dopamine agonists) as first-line ^[19]. This is unique among functioning pituitary adenomas. For ALL other functioning adenomas — including GH-secreting, ACTH-secreting, and TSH-secreting — surgery is first-line. Do not confuse the management of prolactinoma with acromegaly.

5. Medical Therapy (Second Line)

Medical therapy is second-line ^[1], used when:

Indications for medical therapy ^[1]:

Not a surgical candidate (medical comorbidities, large unresectable tumours)

Bridging for radiotherapy to take effect (may need 5–10 years)

Persistent disease after surgery (incomplete biochemical remission)

Adjunctive pre-operative therapy (to shrink tumour / improve anaesthetic risk — e.g. reducing macroglossia for intubation, controlling cardiac disease)

There are three classes of medical therapy for acromegaly, and one class used primarily when there is prolactin co-secretion:

The name: "somatostatin" = soma (body) + statin (standing still / inhibiting). These drugs mimic the natural hormone somatostatin, which inhibits GH release from somatotrophs.

Drug	Formulation	Mechanism
Octreotide LAR (Sandostatin LAR)	IM injection every 4 weeks ^[1]	Binds somatostatin receptors (especially SSTR2 and SSTR5) on somatotroph adenoma cells → inhibits GH secretion and may reduce tumour size (20–50% shrinkage)
Lanreotide (Somatuline Autogel)	Deep SC injection every 4 weeks	Same mechanism as octreotide
Pasireotide LAR	IM injection every 4 weeks	"Pan-somatostatin analogue" — binds SSTR1, 2, 3, 5 (broader receptor binding). More effective in SSA-resistant adenomas (especially those with low SSTR2 expression) but with more metabolic side effects

Aspect	Detail
Efficacy	Normalises IGF-1 in ~55–65% of patients (first-generation SSAs). Pasireotide may achieve control in some octreotide/lanreotide-resistant cases
Tumour shrinkage	20–50% reduction in tumour volume (significant shrinkage in ~20–30%)
Side effects	Nausea/vomiting, gallstones (SSAs inhibit CCK and gallbladder motility → bile stasis → cholelithiasis in 15–30%), impaired glucose tolerance (SSAs inhibit insulin secretion — especially pasireotide, which has a particularly high risk of hyperglycaemia) ^[1], injection site reactions, abdominal cramps, diarrhoea/steatorrhoea

Why Gallstones with SSAs?

Somatostatin normally inhibits CCK release and gallbladder contraction. SSAs therefore reduce gallbladder motility → bile stasis → gallstone formation. Some centres recommend prophylactic cholecystectomy or ursodeoxycholic acid for patients on long-term SSAs, but most adopt a watch-and-treat approach.

Densely granulated vs. sparsely granulated: Densely granulated somatotroph adenomas have high SSTR2 expression → respond well to first-generation SSAs. Sparsely granulated tumours have lower SSTR2 → may need pasireotide (broader SSTR binding) or alternative agents.

Drug	Formulation	Mechanism
Pegvisomant	SC injection daily	A modified GH molecule that binds the GH receptor but blocks signal transduction (competitive antagonist). "Peg" = PEGylated (polyethylene glycol conjugated to extend half-life); "vis" = from GH (growth/vis); "omant" = monoclonal antibody-derived

Aspect	Detail
Efficacy	Normalises IGF-1 in > 90% of patients (the most effective single agent for biochemical control)
Tumour effect	Does NOT reduce tumour size (blocks peripheral GH action but doesn't act on the adenoma itself). May theoretically allow tumour growth (loss of IGF-1 negative feedback → ↑ GH from adenoma) — requires MRI surveillance
Side effects	Deranged LFTs (↑transaminases) ^[1] — requires regular hepatic monitoring. Injection site reactions. Lipohypertrophy
Availability	Not available in HA (Hong Kong Hospital Authority) ^[1] — an important local exam point. Available in private sector and some overseas centres
Monitoring	Follow IGF-1 (NOT GH — because GH levels are actually elevated on pegvisomant due to loss of negative feedback; IGF-1 is the correct monitoring parameter)

Pegvisomant — Exam Pearl

Pegvisomant is not available in HA ^[1]. It is the most efficacious single agent (normalises IGF-1 in > 90%), but its use in Hong Kong public hospitals is limited. It works at the receptor level (not the pituitary level), so it does NOT shrink the tumour and GH levels may paradoxically rise.

Drug	Formulation	Mechanism
Bromocriptine	PO	D2 receptor agonist. D2 receptors are present in some GH-secreting adenomas ^[1], and these tumours may co-secrete GH and prolactin ^[1]
Cabergoline	PO (once or twice weekly)	Same class, longer-acting, better tolerated

Aspect	Detail
Efficacy	Normalises IGF-1 in only ~10–30% of patients (as monotherapy). Most effective when there is GH–prolactin co-secreting tumour ^[1]^[3]^[19]
Side effects	Nausea/vomiting, postural hypotension, constipation, psychosis (dopamine is a neurotransmitter — excessive stimulation can cause hallucinations), retroperitoneal fibrosis (rare, mainly with high-dose ergot-derived dopamine agonists like cabergoline) ^[1]
Niche role	Best suited for mild disease with modest IGF-1 elevation, especially if co-secreting PRL. May be used as adjunct to SSAs. Oral formulation is an advantage over injections

Class	Example	Route	IGF-1 Normalisation	Tumour Shrinkage	Key Side Effects	Availability in HA
Somatostatin analogues	Octreotide LAR, Lanreotide, Pasireotide	IM/SC Q4 weeks	55–65%	Yes (20–50%)	N/V, gallstones, impaired glucose tolerance (especially pasireotide)	Yes
GH receptor antagonist	Pegvisomant	SC daily	> 90%	No	Deranged LFTs	Not available in HA
Dopamine agonists	Bromocriptine, Cabergoline	PO	10–30%	Minimal (unless prolactinoma)	N/V, postural hypotension, constipation, psychosis, retroperitoneal fibrosis	Yes

Medical Therapy for Acromegaly — High Yield Table for SAQ

This table is directly from the lecture/senior notes ^[1] and is a favourite SAQ topic. Know the three classes, their mechanisms, routes, efficacy, and key side effects.

Key distinctions:

SSAs = most commonly used first-line medical therapy; cause gallstones and ↓ insulin
Pegvisomant = most efficacious but does NOT shrink tumour, not in HA
Dopamine agonists = oral, low efficacy as monotherapy, useful if co-secreting PRL

Stereotactic radiotherapy (RT) is used if refractory to medical therapy ^[3], or as adjuvant RT if persistent elevated IGF-1 (residual adenoma after resection is common) ^[1].

Aspect	Detail
Role	Third-line. Used when surgery has failed and medical therapy is inadequate or not tolerated
Types	Stereotactic radiosurgery (SRS) — e.g. Gamma Knife surgery ^[1], CyberKnife, proton beam. Single high-dose focused radiation. Fractionated external beam radiotherapy (EBRT) — conventional; used if tumour too close to optic chiasm for SRS (need ≥ 3–5 mm separation)
Mechanism	Radiation damages DNA of adenoma cells → progressive cell death → gradual reduction in GH secretion over months–years
Efficacy	Biochemical remission in 50–60% at 10 years. Can take 5–10 years to achieve full effect ^[1]^[3]
Bridging	During the latency period, medical therapy (SSA or pegvisomant) is continued as a bridge ^[1]
Side effects	Hypopituitarism (most significant — 50–80% develop one or more new pituitary deficits over 10 years; cumulative and progressive), optic neuropathy (rare with modern stereotactic techniques), cerebrovascular disease (small increased long-term risk), secondary brain tumours (very rare; with older conventional RT)

Indication	Explanation
Residual adenoma post-surgery + uncontrolled on medical therapy	Most common scenario for RT
Patient refusing further surgery or not a surgical candidate	RT as an alternative definitive local treatment
Aggressive / growing residual tumour despite medical therapy	Growth control

7. Special Situations

In some patients with severe, active acromegaly and significant comorbidity (e.g. severe cardiomyopathy, uncontrolled DM, severe OSA with macroglossia making intubation difficult), pre-operative SSA therapy for 3–6 months can:

Reduce GH/IGF-1 → improve cardiac function, glucose control
Reduce soft tissue swelling (including macroglossia) → safer anaesthesia/intubation
May reduce tumour size → improve surgical outcome

OSA is a predisposing factor that requires management in acromegaly ^[20]. Treatment of the underlying acromegaly (surgery, SSAs) reduces macroglossia and oropharyngeal soft tissue → may improve OSA. In the interim, nocturnal nCPAP is the mainstay. Weight reduction, avoidance of alcohol/hypnotics, and sleep hygiene also apply ^[20].

Complication	Management
Hypertension	Treat as per standard guidelines (ACEi/ARB, CCB, beta-blockers). Often improves with biochemical control
Diabetes / IGT	Metformin first-line; be aware that SSAs (especially pasireotide) may worsen glucose control
Arthropathy	Analgesia, physiotherapy. Bony changes are irreversible. Joint replacement if severe
Cardiomyopathy	Standard heart failure management (diuretics, ACEi/ARB, beta-blockers). Echocardiographic monitoring
CRC screening	Colonoscopy at diagnosis then every 3–5 years depending on findings ^[1]^[2]^[3]
OSA	nCPAP, treat underlying acromegaly ^[20]

Monitoring ^[1]:

Parameter	Frequency	Target
Clinical symptoms and signs	Every visit	Resolution of hyperhidrosis, headache; soft tissue regression
Annual random GH	Annually	< 1 ng/mL (ideally < 0.4 ng/mL)
Annual IGF-1	Annually	Normalised to age-adjusted range
Annual pituitary hormone profile	Annually	Detect new hypopituitarism (from surgery, RT, or tumour compression)
Colonoscopy	At diagnosis then Q3–5 years	Polyp / CRC surveillance
MRI pituitary	(Not routine) ^[1] — at 3–6 months post-surgery; then only if indicated (rising IGF-1, new symptoms)	Residual/recurrent tumour
Echocardiography	As clinically indicated	LVH regression, diastolic function
OGTT / HbA1c	Annually or as indicated	DM/IGT monitoring
Visual field perimetry	Post-surgery; then if residual tumour or symptom change	Visual field status

Line	Modality	Key Details
1st line	Transsphenoidal surgery	Cure rates: 80–90% micro, < 50% macro ^[3]. Can repeat if residual tumour
2nd line	Medical therapy	SSAs (octreotide, lanreotide, pasireotide), GH receptor antagonist (pegvisomant — not available in HA ^[1]), dopamine agonists (if co-secreting PRL)
3rd line	Stereotactic radiotherapy (e.g. Gamma Knife) ± EBRT	Takes 5–10 years for full effect ^[1]^[3]; medical therapy bridges the gap; main long-term risk = hypopituitarism

High Yield Summary — Management of Acromegaly

First-line: Transsphenoidal surgery (transnasal endoscopic preferred)

Indications: all functioning adenomas, macroadenomas, mass effect, visual field loss, pituitary apoplexy ^[19]
Cure: 80–90% microadenoma; < 50% macroadenoma ^[3]
Complications: hypopituitarism, DI (transient > permanent), CSF rhinorrhoea, recurrence

Second-line: Medical therapy

SSAs (octreotide LAR, lanreotide, pasireotide) — IM/SC Q4 weeks; S/E: gallstones, ↓insulin
Pegvisomant (GH receptor antagonist) — SC daily; most effective ( > 90%) but NOT in HA; S/E: deranged LFTs
Dopamine agonists (bromocriptine, cabergoline) — PO; only 10–30% efficacy; useful if co-secreting PRL

Third-line: Stereotactic RT (Gamma Knife) or EBRT

Takes 5–10 years for full effect; bridge with medical therapy
Main risk: progressive hypopituitarism

Monitoring: Annual IGF-1, random GH, pituitary profile, colonoscopy. MRI pituitary not routine ^[1]

Active Recall - Management of Acromegaly

Acromegaly is not simply a cosmetic or musculoskeletal disorder — it is a systemic disease with multi-organ complications that drive excess morbidity and mortality. Overall mortality is 1.72× that of the general population, mainly due to cardiovascular risk ^[2]^[3]. Understanding the complications is essential because (a) they are often the presenting features, (b) they must be actively screened for and managed, and (c) achieving biochemical control reduces — but does not eliminate — many of these risks.

The complications are referenced in the Introduction to Endocrine Investigations lecture slide ("Complications of Acromegaly") ^[21] and detailed across the senior notes ^[1]^[2]^[3]^[5].

1. Cardiovascular Complications (Leading Cause of Death)

Cardiovascular disease is the principal driver of excess mortality in acromegaly (CV mortality 2×) ^[2].

Aspect	Detail
Prevalence	HTN occurs in ~40% of acromegaly patients ^[1]^[2]
Pathophysiology	GH/IGF-1 excess causes hypertension through multiple mechanisms: (1) Direct renal sodium retention — GH stimulates Na⁺/K⁺-ATPase and ENaC in the renal tubule → expanded plasma volume; (2) Increased peripheral vascular resistance — IGF-1 promotes vascular smooth muscle hypertrophy; (3) Insulin resistance and hyperinsulinaemia → sympathetic activation → vasoconstriction; (4) OSA → intermittent hypoxia → sympathetic surges → sustained HTN
Clinical significance	Acromegaly is listed as an endocrine cause of secondary hypertension alongside Conn syndrome, Cushing's syndrome, and pheochromocytoma ^[10]. HTN is a sign of active acromegaly ^[1] and often improves (but may not normalise) with biochemical control
Screening/Management	Regular BP monitoring (office + home/ABPM). Treat per standard guidelines (ACEi/ARB preferred given frequent co-existing DM; CCB, beta-blockers as adjuncts)

Aspect	Detail
Pathophysiology	GH/IGF-1 have a direct trophic effect on cardiomyocytes → concentric left ventricular hypertrophy (LVH) with myocardial fibrosis (excess collagen deposition). This progresses through three stages: (1) Early: concentric LVH with hyperkinetic ventricle (increased contractility); (2) Intermediate: diastolic dysfunction (impaired relaxation due to fibrosis and hypertrophy); (3) Late: systolic dysfunction → dilated cardiomyopathy → heart failure
Findings	LVH, cardiomyopathy with diastolic HF ^[2]^[3]. Echocardiography shows concentric LVH, E/A ratio reversal (diastolic dysfunction), and eventually reduced LVEF
Reversibility	Early LVH and diastolic dysfunction are partially reversible with biochemical control (GH/IGF-1 normalisation). Once significant fibrosis and systolic dysfunction develop, changes become irreversible

Aspect	Detail
Prevalence	Up to 75% of acromegaly patients have some degree of valvular abnormality (usually mild)
Pathophysiology	GH/IGF-1 → GAG and collagen deposition in valve leaflets → thickening and regurgitation. Most commonly aortic and mitral regurgitation
Clinical note	VHD is listed as a cardiovascular complication ^[2]. Rarely haemodynamically significant but should be monitored

GH-induced myocardial fibrosis creates a substrate for re-entrant arrhythmias
Increased prevalence of complex ventricular ectopics and atrial fibrillation
Contributes to sudden cardiac death risk

Combination of HTN, dyslipidaemia, DM, and insulin resistance creates a highly atherogenic milieu
Coronary artery disease is a significant contributor to CV mortality
IHD is listed as a complication of acromegalic cardiomyopathy ^[1]

Cardiovascular Complications — The #1 Killer

The main cause of excess mortality in acromegaly is cardiovascular disease ^[2]^[3]. The combination of HTN (40%), LVH, cardiomyopathy with diastolic HF, VHD, and CV mortality (2×) ^[2] underscores why aggressive cardiovascular risk management is essential — not just treating GH excess, but actively managing BP, lipids, and glucose.

2. Metabolic Complications

Aspect	Detail
Prevalence	IGT ~40%, T2DM ~20% ^[1]^[2]
Pathophysiology	GH is a counter-regulatory hormone to insulin. Excess GH → (1) ↑ hepatic gluconeogenesis; (2) ↑ lipolysis → ↑ free fatty acids → lipotoxicity in muscle and pancreatic β-cells; (3) ↓ peripheral glucose uptake (↓ insulin sensitivity in skeletal muscle). These together cause secondary insulin resistance ^[1]. Over time, pancreatic β-cells cannot compensate → progression from IGT to frank DM
Clinical features	Acanthosis nigricans (hyperinsulinaemia → keratinocyte proliferation via IGF-1 receptor), polyuria, polydipsia. Acromegaly is listed as an endocrinopathy causing secondary DM ^[9]
Screening	OGTT or HbA1c at diagnosis and annually. Note that SSA treatment (especially pasireotide) may worsen glucose control because SSAs also inhibit insulin secretion
Management	Metformin first-line for DM/IGT. SGLT2 inhibitors and GLP-1 RAs are useful adjuncts given cardiovascular/renal benefits. Biochemical control of acromegaly itself improves insulin sensitivity

Aspect	Detail
Pattern	↑ lipids ^[2]^[3] — typically ↑ triglycerides (due to GH-driven lipolysis → ↑ FFA flux → hepatic VLDL production) and ↓ HDL. LDL may be variable
Significance	Contributes to accelerated atherosclerosis and IHD
Management	Statin therapy if indicated by cardiovascular risk. Improves partly with GH normalisation

Aspect	Detail
Findings	↑ Ca, ↑ PO₄ ^[2]^[3]
Pathophysiology	GH → stimulates renal 1α-hydroxylase → ↑ 1,25-dihydroxyvitamin D₃ → ↑ intestinal calcium absorption → hypercalcaemia. GH also directly ↑ renal tubular phosphate reabsorption → hyperphosphataemia
Consequence	Renal stones (hypercalciuria) ^[2] — excess calcium filtered and excreted in urine. Also consider that hypercalcaemia itself can cause polyuria (nephrogenic DI), constipation, and confusion if severe
Screening	Serum Ca, PO₄, 24-hour urine calcium at diagnosis. If MEN-1 suspected, also check PTH

3. Respiratory Complications

Aspect	Detail
Prevalence	OSA occurs in ~50% of acromegaly patients ^[2]
Pathophysiology	Macroglossia and mucosal hypertrophy of the oropharyngeal tissues → upper airway narrowing → collapse during sleep ^[5]. Additional factors: soft tissue thickening of pharyngeal walls, subglottic narrowing. Central sleep apnoea also occurs (GH alters central respiratory drive)
Consequences	Sleep fragmentation → excessive daytime sleepiness → road traffic accidents, neurocognitive impairment. Sympathetic activation → secondary hypertension. Chronic intermittent hypoxia → oxidative stress → accelerated atherosclerosis, arrhythmias. In severe cases: cor pulmonale ^[20]
Screening	Polysomnography ^[10] — gold standard. Epworth Sleepiness Scale as initial clinical screen
Management	Nocturnal nCPAP (the mainstay); treat underlying acromegaly (↓ macroglossia with biochemical control); weight reduction; avoid alcohol/sedatives ^[20]. Acromegaly is listed as a predisposing factor for OSA that requires management ^[20]

Macroglossia, subglottic stenosis, and vocal cord thickening create difficult airway situations
Anaesthetists must be alerted pre-operatively — fibreoptic intubation may be required
This is clinically relevant for transsphenoidal surgery planning

4. Musculoskeletal Complications

Aspect	Detail
Prevalence	Up to 70% of patients
Pathophysiology	Hypertrophic arthropathy due to enlargement of synovial tissue and cartilage ^[2]^[3]. Initially, GH/IGF-1 → chondrocyte proliferation → cartilage thickening (widened joint space on X-ray). Over time, the overgrown cartilage becomes biomechanically abnormal → fissuring, ulceration → secondary degenerative osteoarthritis. Weight-bearing joints most affected (knees, hips, spine)
Clinical features	Bilateral knee OA ^[5], back pain (kyphosis from vertebral body overgrowth and disc degeneration), joint stiffness. Presents at a younger age than typical primary OA — a red flag that should prompt consideration of acromegaly
Reversibility	Irreversible — bony and cartilaginous changes persist even after biochemical control. This is one of the most disabling long-term complications
Management	Analgesia, physiotherapy, joint replacement if severe. Control of acromegaly prevents further progression

Aspect	Detail
Pathophysiology	GH/IGF-1 promote calcium pyrophosphate dihydrate (CPPD) crystal deposition in cartilage ^[2] — likely via increased pyrophosphate production in chondrocytes
Clinical	Acute crystal arthropathy (pseudogout attacks), chondrocalcinosis on X-ray

Aspect	Detail
Prevalence	Up to 50% of patients
Pathophysiology	IGF-1 → soft tissue and synovial overgrowth within the rigid carpal tunnel → compression of the median nerve
Reversibility	Partially reversible with biochemical control (soft tissue regression). May still require surgical carpal tunnel release if severe or persistent

5. Neoplastic Complications

Aspect	Detail
Risk	↑ risk of colon CA, polyps, diverticulosis ^[1]^[2]^[3]
Pathophysiology	IGF-1 acts as a growth factor for colonic mucosal cells ^[8] → promotes cell proliferation and inhibits apoptosis → ↑ adenomatous polyp formation → adenoma–carcinoma sequence → colorectal cancer. Also ↑ intestinal transit time (visceromegaly → colonic lengthening) → stasis → diverticulosis
Screening	Colonoscopy at diagnosis ^[2]^[3]. Repeat every 3–5 years depending on findings and disease activity. If polyps found, follow standard polypectomy + surveillance protocols
Key exam point	Acromegaly (and DM) are endocrine risk factors for CRC ^[8]. This is a frequent SAQ / MCQ topic

Type	Evidence
Thyroid cancer	Acromegalic goitre (diffuse/multinodular) may harbour thyroid nodules; modest ↑ risk of differentiated thyroid cancer
Breast cancer	Some epidemiological association with ↑ IGF-1
Overall cancer risk	↑ risk of other malignancy ^[2] — a general increase in cancer incidence/mortality, though data are inconsistent across studies. IGF-1's mitogenic and anti-apoptotic effects provide a plausible biological rationale

Colonoscopy Is Mandatory in Acromegaly

Colonoscopy for any colonic tumours ^[2]^[3] — this is one of the key complication-screening investigations at diagnosis and during follow-up. Do not forget this in an SAQ asking about "investigations for a patient with acromegaly."

6. Neurological / Mass Effect Complications

These complications arise from the pituitary adenoma itself (local effects), not from GH excess per se.

Aspect	Detail
Mechanism	Suprasellar extension of the macroadenoma → compression of the optic chiasm (the crossing nasal retinal fibres) → bitemporal hemianopia ^[2]^[3]. The patient loses temporal visual fields bilaterally → bumps into objects/people on the side (the very scenario described in the lecture: "I keep on bumping into people on my side" ^[6]^[7])
Progression	Initially upper temporal quadrantanopia (chiasm compressed from below) → progresses to full bitemporal hemianopia → if untreated, can progress to blindness
Screening	Formal visual field perimetry (Humphrey or Goldmann) at diagnosis and post-surgery
Reversibility	Often partially or fully reversible with surgical decompression of the chiasm. Recovery depends on duration and severity of compression

Aspect	Detail
Mechanism	Lateral extension into the cavernous sinus → compression of CN III, IV, V₁, V₂, VI ^[2] → diplopia, ptosis, facial numbness
Clinical	CN III palsy most common → ptosis + "down and out" eye + mydriasis

Aspect	Detail
Mechanism	Large adenoma compresses surrounding normal pituitary tissue → progressive loss of anterior pituitary hormones. Typical order of loss: GH > LH/FSH > TSH > ACTH (but in acromegaly, GH is paradoxically elevated, so the patient may present with hypogonadism, hypothyroidism, or adrenal insufficiency while GH is high)
Also caused by	Treatment itself — transsphenoidal surgery and radiotherapy both carry risk of iatrogenic hypopituitarism
Clinical features	Fatigue, sexual dysfunction (↓ LH/FSH → hypogonadism), cold intolerance (↓ TSH → secondary hypothyroidism), postural hypotension (↓ ACTH → secondary adrenal insufficiency — no hyperpigmentation, unlike primary Addison's, because ACTH is low not high)
Screening	Full pituitary hormone profile at diagnosis and annually post-treatment ^[1]

Present in up to 60% of patients
Mechanism: dural stretching by tumour, raised intrasellar pressure, and possibly direct GH/IGF-1 effects on pain pathways
Often improves dramatically post-surgery (even microadenoma patients report headache relief)

7. Endocrine Complications

Aspect	Detail
Prevalence	~30% of acromegaly patients ^[2]
Mechanism	Two possibilities: (1) Co-secretion of PRL from a mammosomatotroph adenoma; (2) Stalk effect — tumour compresses the pituitary stalk, interrupting dopamine delivery from hypothalamus to lactotrophs → loss of tonic dopamine inhibition → ↑ PRL ^[2]
Clinical	Galactorrhoea, menstrual irregularity/amenorrhoea (women), erectile dysfunction/↓ libido (men)
Distinction	Stalk effect PRL is usually < 100–150 µg/L; co-secretion can be higher. Very high PRL ( > 200 µg/L) suggests true co-secretion or a separate prolactinoma

Aspect	Detail
Findings	Diffuse or multinodular goitre; often non-toxic but can be toxic ^[2]^[3]
Pathophysiology	IGF-1 is a potent mitogen for thyroid follicular cells → follicular cell proliferation → goitre. If autonomous thyroid nodules develop, can cause hyperthyroidism (toxic)
Management	Thyroid function tests, thyroid ultrasound if nodular. Treat hyperthyroidism if present

Complication	Mechanism
Skin tags (acrochordons)	GH/IGF-1–driven fibroblast proliferation. Epidemiological association: ↑ skin tags correlates with ↑ risk of colonic polyps — so finding many skin tags should raise suspicion for acromegaly AND prompt colonoscopy
Acanthosis nigricans	Hyperinsulinaemia (secondary to GH-induced insulin resistance) → insulin and IGF-1 stimulate keratinocyte and fibroblast proliferation → velvety hyperpigmented plaques in flexural areas
Hyperhidrosis	Sweat gland hypertrophy — a marker of active disease; resolves with biochemical control

Depression and anxiety: common; multifactorial (disfigurement, chronic disease, sleep disturbance, hormonal effects)
Cognitive impairment: may be related to OSA, chronic disease, or direct GH/IGF-1 effects on the brain
Body image concerns: irreversible bony changes persist even after treatment
Reduced quality of life: documented on validated questionnaires (AcroQoL); does not fully normalise even with biochemical control

System	Specific Complications	Pathophysiology	Reversible?
Cardiovascular	HTN (40%), LVH, cardiomyopathy with diastolic HF, VHD, IHD, CV mortality (2×) ^[2]	Na retention, vascular remodelling, myocardial hypertrophy/fibrosis, accelerated atherosclerosis	Partially (early LVH/diastolic dysfunction); late fibrosis/systolic failure irreversible
Metabolic	IGT (40%), T2DM (20%), ↑lipids, ↑Ca, ↑PO₄, renal stones ^[2]	GH counter-regulatory to insulin; ↑1,25-diOH VitD; ↑ tubular PO₄ reabsorption	Largely reversible with biochemical control
Respiratory	OSA (~50%)	Macroglossia, oropharyngeal mucosal hypertrophy	Improves with treatment; may need ongoing CPAP
MSK	OA, hypertrophic arthropathy, pseudogout, CTS	Cartilage/synovial overgrowth, CPPD, soft tissue swelling	Irreversible (bony/cartilage); CTS partially reversible
Neoplastic	↑ CRC, polyps, diverticulosis; ↑ other malignancy ^[2]	IGF-1 mitogenic on colonic epithelium	N/A — requires screening and surveillance
Neurological / Mass effect	Bitemporal hemianopia, CN palsies, hypopituitarism, headache	Tumour compression of chiasm, cavernous sinus, normal pituitary	Visual fields often recover post-surgery; pituitary function may not
Endocrine	Hyperprolactinaemia (~30%), goitre	Co-secretion/stalk effect; IGF-1 mitogenic on thyrocytes	PRL normalises with tumour removal; goitre may persist
Dermatological	Skin tags, acanthosis nigricans, hyperhidrosis	GH/IGF-1 proliferative effects; insulin resistance	Hyperhidrosis resolves; skin tags and AN improve
Psychological	Depression, anxiety, ↓ QoL	Multifactorial	Partially improves

High Yield Summary — Complications of Acromegaly

Overall mortality 1.72× general population, mainly due to cardiovascular risk ^[2]^[3].

Cardiovascular (leading cause of death):

HTN (40%), LVH, cardiomyopathy with diastolic HF, CV mortality (2×), VHD ^[2]
Pathophysiology: Na retention, vascular remodelling, myocardial fibrosis, accelerated atherosclerosis

Metabolic:

IGT (40%), T2DM (20%) — GH = counter-regulatory hormone → insulin resistance
↑ lipids, ↑ Ca, ↑ PO₄, renal stones (hypercalciuria) ^[2]

Respiratory:

OSA (~50%) — from macroglossia and oropharyngeal mucosal hypertrophy ^[5]

MSK (irreversible):

Hypertrophic arthropathy, OA, pseudogout, CTS ^[2]

Neoplastic:

↑ risk of colon CA, polyps, diverticulosis — IGF-1 as growth factor for colonic mucosal cells ^[8]
Colonoscopy at diagnosis and Q3–5 years ^[2]^[3]

Mass effect: bitemporal hemianopia, CN palsies, hypopituitarism

Endocrine: hyperprolactinaemia (~30%), goitre

Achieving biochemical control (normal IGF-1 + GH) reduces mortality towards baseline and reverses metabolic and soft tissue complications, but bony/cartilage changes are irreversible.

Active Recall - Complications of Acromegaly

^[1] Senior notes: Maksim Medicine Notes.pdf (Endocrinology — Acromegaly section, p108) ^[2] Senior notes: Ryan Ho Endocrine.pdf (Section 5.2.3 Acromegaly — Complications, p111) ^[3] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.8.4.3 Acromegaly — Complications, p444) ^[5] Senior notes: Block A - Introduction to Endocrine investigations.pdf (facial features, OSA mechanism, p8) ^[6] Lecture slides: GC 067. I keep on bumping into people on my side.pdf ^[7] Lecture slides: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf ^[8] Senior notes: Maksim Surgery Notes.pdf (CRC risk factors — acromegaly and IGF-1, p103) ^[9] Senior notes: Block A - Polyuria and polydipsia_ glucose metabolism; diabetes mellitus; diabetic ketoacidosis.pdf (endocrinopathies causing DM, p8) ^[10] Senior notes: Block A - Endocrine Data Interpretation.pdf (secondary hypertension — acromegaly, p4) ^[20] Senior notes: Ryan Ho Respiratory.pdf (OSA management including acromegaly as predisposing factor, p160–161) ^[21] Lecture slides: IntroEndoInvestigations For Students (updated 102025).pdf (Complications of Acromegaly slide, p19)

High Yield Summary

Definition: Acromegaly = GH excess in adults (post-epiphyseal fusion); Gigantism = GH excess in children.

Aetiology: GH-secreting pituitary adenoma > 95%. Rare: GHRH-secreting hypothalamic tumours, ectopic GH/GHRH from neuroendocrine tumours.

Associations: MEN-1, Carney complex (cardiac myxoma + spotted pigmentation), McCune-Albright (precocious puberty + café-au-lait + fibrous dysplasia).

Key Clinical Features (SAQ!):

Mass effect: headache, bitemporal hemianopia, CN palsies, hypopituitarism
Soft tissue: coarse facies, prognathism, macroglossia, thick skin/lips (collagen + GAG deposition), deepening voice, CTS, OSA (~50%)
Acral: large hands (spade-like, spatulate fingers), large feet (thick heel pads), ↑ring/shoe size
Skin: hyperhidrosis (> 80%) = active disease marker, hirsutism, skin tags, acanthosis nigricans
MSK: OA (especially knees), hypertrophic arthropathy, pseudogout
CVS: HTN (40%), LVH, cardiomyopathy, diastolic HF → main cause of excess mortality
Metabolic: IGT (40%), DM (20%), ↑lipids, ↑Ca, ↑PO₄, renal stones
Organomegaly: goitre, hepatosplenomegaly, ↑risk of CRC (colonoscopy needed)
Hyperprolactinaemia (~30%): galactorrhoea, menstrual irregularity

Screening: IGF-1 (not random GH — too variable, short half-life).

Gold standard diagnosis: OGTT with GH levels — GH fails to suppress (nadir > 0.4–1 ng/mL) or paradoxical increase (30%).

Imaging: Pituitary MRI. Also full pituitary hormone profile and colonoscopy.

High Yield Summary — Differential Diagnosis of Acromegaly

Clinical mimics: Hypothyroidism (puffiness, macroglossia, CTS), Cushing's syndrome (facial change, HTN, DM), pachydermoperiostosis, Paget's disease of bone.

Aetiological DDx of confirmed GH excess:

GH-secreting pituitary adenoma > 95%
Ectopic GHRH (neuroendocrine tumours — bronchial/pancreatic carcinoid, SCLC, MTC, phaeochromocytoma)
Hypothalamic GHRH-secreting ganglioneuroma
Ectopic GH (pancreatic islet-cell tumour, lymphoma) — very rare

Key distinguishing point: If MRI shows no discrete adenoma, measure plasma GHRH to exclude ectopic source. Ectopic GHRH causes somatotroph hyperplasia, not adenoma.

Acromegaly as a DDx of other presentations: Secondary hypertension, CTS, secondary DM, OSA in non-obese patient, premature OA.

Endocrine causes of secondary hypertension (high-yield exam list): Acromegaly, Conn syndrome, Cushing's syndrome, pheochromocytoma ^[10].

High Yield Summary — Diagnosis of Acromegaly

Diagnostic Approach (in order):

Clinical suspicion → coarse features, large hands/feet, sweating, HTN, OSA, DM, visual field loss
Screen: Serum IGF-1 (not random GH — GH has diurnal rhythm, short half-life, influenced by stress/exercise) ^[1]^[10]
Confirm: 75g OGTT with serial GH — GH nadir > 0.4–1 ng/mL confirms diagnosis; ~30% show paradoxical GH rise ^[2]^[3]
Localise: Pituitary MRI with gadolinium — biochemistry BEFORE imaging ^[17]
If no adenoma on MRI: measure plasma GHRH → exclude ectopic GHRH source ^[2]^[11]
Full workup: pituitary hormone profile (PRL, cortisol, TSH/fT4, FSH/LH), visual fields, colonoscopy, echo, OGTT for DM, sleep study

Key principle: In endocrine, biochemistry before imaging — resolution is too high with modern imaging, may find incidentalomas unrelated to the condition ^[17].

High Yield Summary — Management of Acromegaly

First-line: Transsphenoidal surgery (transnasal endoscopic preferred)

Indications: all functioning adenomas, macroadenomas, mass effect, visual field loss, pituitary apoplexy ^[19]
Cure: 80–90% microadenoma; < 50% macroadenoma ^[3]
Complications: hypopituitarism, DI (transient > permanent), CSF rhinorrhoea, recurrence

Second-line: Medical therapy

SSAs (octreotide LAR, lanreotide, pasireotide) — IM/SC Q4 weeks; S/E: gallstones, ↓insulin
Pegvisomant (GH receptor antagonist) — SC daily; most effective ( > 90%) but NOT in HA; S/E: deranged LFTs
Dopamine agonists (bromocriptine, cabergoline) — PO; only 10–30% efficacy; useful if co-secreting PRL

Third-line: Stereotactic RT (Gamma Knife) or EBRT

Takes 5–10 years for full effect; bridge with medical therapy
Main risk: progressive hypopituitarism

Monitoring: Annual IGF-1, random GH, pituitary profile, colonoscopy. MRI pituitary not routine ^[1]

High Yield Summary — Complications of Acromegaly

Overall mortality 1.72× general population, mainly due to cardiovascular risk ^[2]^[3].

Cardiovascular (leading cause of death):

HTN (40%), LVH, cardiomyopathy with diastolic HF, CV mortality (2×), VHD ^[2]
Pathophysiology: Na retention, vascular remodelling, myocardial fibrosis, accelerated atherosclerosis

Metabolic:

IGT (40%), T2DM (20%) — GH = counter-regulatory hormone → insulin resistance
↑ lipids, ↑ Ca, ↑ PO₄, renal stones (hypercalciuria) ^[2]

Respiratory:

OSA (~50%) — from macroglossia and oropharyngeal mucosal hypertrophy ^[5]

MSK (irreversible):

Hypertrophic arthropathy, OA, pseudogout, CTS ^[2]

Neoplastic:

↑ risk of colon CA, polyps, diverticulosis — IGF-1 as growth factor for colonic mucosal cells ^[8]
Colonoscopy at diagnosis and Q3–5 years ^[2]^[3]

Mass effect: bitemporal hemianopia, CN palsies, hypopituitarism

Endocrine: hyperprolactinaemia (~30%), goitre

Achieving biochemical control (normal IGF-1 + GH) reduces mortality towards baseline and reverses metabolic and soft tissue complications, but bony/cartilage changes are irreversible.

Acromegaly

Definition

Epidemiology

Risk Factors

Anatomy and Function: The Hypothalamic–Pituitary–GH/IGF-1 Axis

3.1 Pituitary Anatomy

3.2 Neighbouring Structures (Why Mass Effect Matters)

3.3 GH Physiology — From First Principles

3.4 Normal GH Suppression by Glucose

Aetiology

Classification

5.1 By Adenoma Size (Radiological)

5.2 By Hormone Co-Secretion

5.3 By Invasiveness (Knosp Classification — Cavernous Sinus Invasion)

5.4 WHO 2022 Classification

Clinical Features

6.1 Symptoms (with Pathophysiological Basis)

A. Symptoms Related to GH/IGF-1 Excess

B. Symptoms Related to Local Mass Effect

6.2 Signs (with Pathophysiological Basis)

A. Facial Signs

B. Hand Signs

C. Feet

D. Skin Signs

E. Musculoskeletal Signs

F. Cardiovascular Signs

G. Visceromegaly

H. Visual Field and Neurological Signs

I. Signs of Hypopituitarism (from Compression)

6.3 Metabolic Consequences (Clinical Features of Comorbidity)

6.4 Signs of Active vs. Inactive Acromegaly

Summary of Clinical Approach to Acromegaly (Pre-Diagnosis)

Active Recall - Acromegaly (Definition, Epidemiology, Aetiology, Clinical Features)

References

Differential Diagnosis of Acromegaly

1. Clinical Mimics of Acromegaly ("Pseudoacromegaly" and Look-Alikes)

2. Aetiological Differential Diagnosis of Confirmed GH/IGF-1 Excess

Systematic Aetiological Classification

How to Distinguish Pituitary vs. Ectopic Source

3. Differential Diagnosis by Presenting Feature

A. Presenting with Secondary Hypertension

B. Presenting with Carpal Tunnel Syndrome

C. Presenting with Diabetes Mellitus / Impaired Glucose Tolerance

D. Presenting with Obstructive Sleep Apnoea

E. Presenting with Bilateral Knee OA / Arthropathy

4. Differential Diagnosis of a Pituitary Mass (When Imaging Reveals an Adenoma)

5. Diagnostic Decision-Making Flowchart

6. DDx Summary Table — Putting It All Together

Active Recall - Differential Diagnosis of Acromegaly

References

Diagnostic Criteria, Algorithm, and Investigations for Acromegaly

1. Principles of Endocrine Investigation — Applied to Acromegaly

2. Diagnostic Criteria for Acromegaly

Step 1: Screening — Serum IGF-1

Step 2: Confirmation — Oral Glucose Tolerance Test (OGTT) with Serial GH

Diagnostic Criteria Summary

3. Complete Diagnostic Algorithm

4. Investigation Modalities — Detailed Breakdown

4.1 Biochemical Investigations

A. Serum IGF-1

B. Random Serum GH

C. 75g OGTT with Serial GH ("Extended OGTT")

D. GH Day Curve (Mean GH)

E. Plasma GHRH

F. Full Pituitary Hormone Profile

4.2 Imaging Investigations

A. Pituitary MRI with Gadolinium Contrast

B. CT Chest and Abdomen

C. CT Adrenals (If Clinically Indicated)

4.3 Complication Screening Investigations

4.4 Genetic / Familial Syndrome Workup

5. Data Interpretation Pearls

Interpreting IGF-1 Results

Interpreting OGTT GH Results

Interpreting Pituitary MRI

6. Summary of Key Investigations

Active Recall - Diagnosis and Investigations of Acromegaly

References

Management of Acromegaly

1. Goals of Treatment