Acromegaly

1. Definition

2. Etiology

• Mixed mammosomatotrope tumors and acidophilic stem cell adenomas secrete both GH and PRL. In acidophilic stem cell adenomas, features of hyperprolactinemia (hypogonadism, galactorrhea) dominate over acromegaly signs.
• GHRH-mediated acromegaly presents with classic acromegaly features, elevated GH, pituitary enlargement on MRI, and pituitary hyperplasia (not adenoma) on pathology. Most common cause: chest/abdominal carcinoid.
• Rarely, ectopic GH secretion from pancreatic, ovarian, lung, or hematopoietic tumors.

3. GH Physiology (Background)

• GH is the most abundant anterior pituitary hormone; somatotropes constitute up to 50% of anterior pituitary cells.
• GHRH (44 amino acids, hypothalamic) - stimulates GH synthesis and release via GPCR/cAMP pathway.
• Ghrelin (octanoylated gastric peptide) - induces GHRH and directly stimulates GH release.
• Somatostatin (SRIF) - inhibits GH secretion; SST2 and SST5 subtypes primarily suppress GH.
• GH secretion is pulsatile, with highest peaks at night (sleep onset).
• GH secretory rates decline markedly with age (~15% of pubertal levels in middle age).
• A single random GH level is not useful - ~50% of daytime samples in healthy subjects are undetectable.

• Protein synthesis and nitrogen retention
• Impairs glucose tolerance (insulin antagonism)
• Stimulates lipolysis - increases circulating fatty acids, reduces omental fat, increases lean body mass
• Promotes Na+, K+, water retention; elevates inorganic phosphate
• Stimulates linear bone growth via epiphyseal prechondrocyte differentiation

• Liver is the major source of circulating IGF-1 (GH-dependent)
• IGF-1 peaks at age 16, then declines >80% with aging
• IGFBP3 is GH-dependent and the major carrier protein for circulating IGF-1
• In acromegaly, IGF-1 levels show a log-linear relationship with circulating GH
• GH receptor signals via JAK/STAT pathway

4. Clinical Features

Acral/Skeletal Features

• Frontal bossing, mandibular enlargement, prognathism
• Widened space between lower incisors
• Increased hand and foot size
• "Spadelike" distal finger tufts
• Large fleshy nose
• Kyphosis, barrel chest (rib enlargement + dorsal kyphosis)

Soft Tissue / Skin

• Soft tissue swelling: increased heel pad thickness, increased shoe/glove size, ring tightening
• Coarse facial features
• Hyperhidrosis (very common)
• Oily skin
• Acanthosis nigricans, skin tags
• Deep, hollow-sounding voice

Cardiovascular (most significant impact)

• Cardiomyopathy with arrhythmia
• Left ventricular hypertrophy
• Decreased diastolic function
• Hypertension
• Overall mortality increased ~3-fold (primarily cardiovascular and cerebrovascular disorders and respiratory disease)
• Untreated acromegaly reduces survival by an average of 10 years

Respiratory

• Upper airway obstruction with sleep apnea in >60% of patients
• Caused by: soft tissue laryngeal airway obstruction AND central sleep dysfunction

Metabolic

• Diabetes mellitus in 25% of patients (GH counteracts insulin)
• Most patients are glucose intolerant

Gastrointestinal / Oncologic

• Colon polyps in up to 1/3 of patients
• Increased mortality from colonic malignancy
• Visceromegaly: cardiomegaly, macroglossia, thyroid gland enlargement

Musculoskeletal (Arthropathy)

• Osteoarthritis affecting knees, shoulders, hips, wrists, fingers - wrist involvement is not prominent in primary OA, making it a distinguishing clue
• Initial: joint space widening (cartilage hypertrophy) → later joint space narrowing as cartilage degrades
• Joint fluid: noninflammatory
• Chondrocalcinosis - calcium pyrophosphate crystals can cause pseudogout attacks
• Back pain (spine hypermobility); radiographs show widened intervertebral disk spaces, anterior osteophytes, ligamental calcification (can mimic DISH)
• Thickened heel pad in 1/3 of patients
• Raynaud's phenomenon in ~1/3
• Carpal tunnel syndrome in ~1/2 of patients (median nerve compression by excess connective tissue)
• Proximal muscle weakness (non-inflammatory GH effect; serum enzymes and EMG normal)

Reproductive / Hormonal

• PRL elevated in ~25% of acromegaly patients (co-secreting tumors)
• Hypogonadism and galactorrhea if acidophilic stem cell adenoma
• Thyroid/gonadotropin/sex steroid levels may be attenuated from tumor mass effects

FIGURE 392-7 - A 22-year-old man with gigantism (left) next to his identical twin, showing increased height, hand, and foot size.

5. Diagnosis

IGF-1

• Age-matched serum IGF-1 is elevated in acromegaly
• Best screening test when clinical features suggest acromegaly
• IGF-1 provides a useful laboratory measure because it integrates overall GH secretion

GH Suppression Test (Gold standard)

• Single random GH is not useful (pulsatile secretion)
• Oral glucose tolerance test (OGTT, 75 g): failure to suppress GH to <0.4 μg/L within 1-2 hours confirms the diagnosis
• With ultrasensitive assays, normal nadir GH is even lower (<0.05 μg/L)
• ~20% of patients show a paradoxical GH rise after glucose
• Using standard assays, glucose suppresses GH to <0.7 μg/L in women and <0.07 μg/L in men

Additional Labs

• PRL: measure in all patients (elevated in ~25%)
• Thyroid function, gonadotropins, sex steroids: may be attenuated due to mass effects
• ACTH reserve testing: defer until after surgery (most patients get glucocorticoid coverage perioperatively)

Imaging

• Pituitary MRI to localize the adenoma
• Most tumors are macroadenomas at presentation

6. Treatment

1. Surgery (First-line)

• Transsphenoidal surgical resection of GH-secreting adenoma is the initial treatment for most patients
• Somatostatin receptor ligands (SRLs) are used as adjuvant therapy

2. Somatostatin Receptor Ligands (SRLs) - Primary medical therapy

• Octreotide (short-acting) and lanreotide (long-acting)
• Act via SST2 and SST5 receptor subtypes to suppress GH
• Reduce GH and IGF-1 levels, improve symptoms
• May shrink tumor in some patients
• Used pre-operatively to improve surgical outcomes, or as primary therapy if surgery is contraindicated/declined

3. Dopamine Agonists

• Cabergoline or bromocriptine
• Less effective than SRLs for GH suppression
• More effective in mixed GH/PRL-secreting tumors
• Oral administration is an advantage

4. GH Receptor Antagonist

• Pegvisomant - a GH analogue that binds to the receptor but cannot signal (competitive antagonist)
• Approved for treatment of acromegaly
• Directly blocks peripheral GH action → lowers IGF-1
• Does not lower GH levels; tumor monitoring still required

5. Radiotherapy

• Used when surgery and medical therapy fail
• Options: conventional radiotherapy, stereotactic radiosurgery (Gamma Knife)
• Effect on GH/IGF-1 may take years
• Risk of hypopituitarism

7. Key Numbers to Remember

8. Acromegaly vs. Gigantism

9. Associations / Syndromes

• MEN-1: GH cell adenoma is one of the pituitary manifestations
• McCune-Albright syndrome: can cause somatotrope hyperfunction
• Carcinoid tumors: most common cause of ectopic GHRH-mediated acromegaly