acromegaly
ACROMEGALY
Acromegaly is a chronic, slowly developing disease with progressive disfigurement and disability. An early diagnosis is difficult as most signs and symptoms are due to long-standing overproduction of growth hormone &/or insulin-like growth factor (IGF-I) causing metabolic, endocrine and morphological changes.
Surgical intervention is the first-line of treatment for almost all patients with acromegaly unless there are contraindications or the patient refuses to undergo the procedure.

Pharmacotherapy

  • Recommended for patients where surgery is not suitable or in patients with persistent disease after surgical resection of adenoma

Somatostatin Analogues (SSA) or Somatostatin Receptor Ligands (SRL)

  • First generation: Lanreotide, Octreotide; second generation: Pasireotide
  • Analogs of naturally occurring somatostatin with similar pharmacological actions but with prolonged duration of action
  • First-generation SRLs are 1st-line pharmacotherapy agents
  • May also be used after surgery has failed to achieve biochemical control
  • May provide disease control, or partial control, in the time between administration of radiation therapy and the onset of maximum benefit attained from radiation therapy
  • Available in long-acting release (LAR) depot and short-acting SC preparations
  • Pasireotide LAR, may be used in patients with clinically relevant residual tumor not suitable for resection and inadequately controlled by first-generation SRL
  • May be combined with dopamine agonists to improve therapeutic efficacy
  • Actions: Bind to somatostatin receptor subtypes 2 and 5 on growth hormone-secreting adenomas to suppress growth hormone secretion
  • Somatostatin analogues are effective in normalizing growth hormone and insulin-like growth factor-I levels in approximately 55% of patients
    • Decrease growth hormone secretion to <2.5 ng/mL in 44% of patients in unselected populations
    • Normalize insulin-like growth factor-I levels in 34% of patients in unselected populations
    • Tumor shrinkage of >20% in approximately 75% of acromegaly patients
  • Advantages: Rapid onset, continued efficacy, with proven safety record
  • Common side effects include cramping and abdominal bloating, with a reduction over the first few months of treatment
  • To properly assess adequacy of treatment and the need for dose titration, it is recommended to have patients remain on the same dose for 3 months (if tolerated by patient)

Dopamine Agonists

  • Eg Bromocriptine, Cabergoline, Quinagolide
  • May be considered particularly in patients with mild biochemical activity (eg modestly elevated serum insulin-like growth factor-I in the absence or concomitant presence of somatostatin analogues therapy)
  • Bind to D2 dopamine receptors expressed on growth hormone-secreting adenoma and reduces growth hormone production
  • Advantages include their low cost and that they are the only orally administered medication available for acromegaly
  • May very occasionally be a first-line therapy post-surgery in selected patients (eg those with markedly elevated prolactin levels and/or modestly elevated growth hormone and insulin-like growth factor-I levels)
    • Cabergoline may be considered in patients with persistent disease after surgery or added to SRL if IGF-1 levels <2.5 times the upper limit of normal
  • An additive therapy to somatostatin analogues in patients partially responsive to a maximum somatostatin analogues dose
    • With combination therapy, approximately 50% of such patients may achieve control of insulin-like growth factor-I and growth hormone levels
  • Bromocriptine was shown to provide benefit in a minority of patients with acromegaly in earlier studies but Cabergoline, a more selective dopamine-2 receptor agonist, may be effective in a larger percentage of patients
  • Repeated prolactin, growth hormone and insulin-like growth factor-I levels should be determined 4-6 weeks after each dosage change of dopamine agonist
  • Potential side effects include gastrointestinal upset, orthostatic hypotension, headache and nasal congestion

Growth Hormone Receptor Antagonist (GHRA)

Pegvisomant

  • A growth hormone receptor antagonist that competes with endogenous growth hormone for its receptor and prevents functional dimerization and signal transduction by the growth hormone receptor
  • Indicated in patients with persistently elevated insulin-like growth factor-I levels despite maximal therapy with other treatment modalities
    • Effective in normalizing insulin-like growth factor-I levels in >90% of patients, including those who are partially or completely resistant to other medical therapies
  • Often used as medical therapy in patients with inadequate response to or partial tolerability to somatostatin analogues
  • Potential side effects include flu-like illness, allergic reactions and elevated liver enzymes
    • Serial liver function test monitoring is recommended: monthly for the 1st 6 months; quarterly for the next 6 months; then biannually
    • Patients with elevated baseline LFTs require more frequent monitoring
  • Serum growth hormone levels are not specific and should not be monitored in patients receiving Pegvisomant
    • Endogenous growth hormone levels increase with Pegvisomant administration and Pegvisomant may be cross-measured in growth hormone assays

Combination Therapy

  • In patients with partial or inadequate response to somatostatin analogues therapy, Cabergoline may be useful for further lowering of insulin-like growth factor-I or growth hormone levels
  • In patients with a partial response to somatostatin analogues therapy, addition of daily, weekly or twice weekly Pegvisomant may be beneficial
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