8 Endocrine Case Reports

• Thyroid-stimulating hormone (TSH)


  1.3 mIU/L (normal range 0.5 mIU/L to 5 mIU/L)
• Free thyroxine (fT4)


  8.2 pmol/L (normal range 8.7 pmol/L to 16 pmol/L)
• Complete blood count, electrolyte, glucose, creatinine, liver enzyme and tissue transglutaminase antibody levels were normal
• Serum IGF-I


  127 ng/ml (normal range for a 16 year old is182 to 780 ng/mL)
• Growth hormone deficiency (GHD)


  Also known as dwarfism or pituitary dwarfism, a condition caused by insufficient amounts of growth hormone in the body
• Children with GHD have abnormally short stature with normal body proportions
• Disproportionate dwarfism


  Body size is disproportionate, some parts of the body are small, and others are of average size or above-average size, disorders inhibit the development of bones
• Proportionate dwarfism


  Body is proportionately small, all parts of the body are small to the same degree and appear to be proportioned like a body of average stature, medical conditions present at birth or appearing in early childhood limit overall growth and development
• Gigantism


  Condition characterized by extreme physical size and stature, originates during infancy, childhood or adolescence, when epiphyseal growth plates remain open, often due to hypersecretion of growth hormone (GH) by the anterior pituitary gland

  
• Acromegaly


  Rare disorder caused by excessive growth hormone production (GH), most commonly from an adenoma of the anterior pituitary gland

  
• Insulin-like Growth Factor 1 (IGF-1)


  Causes the characteristic overgrowth of certain tissues resulting in coarsening of facial features, enlarging hands and feet, as well as effects on multiple systems throughout the body
• If the levels of GH are increased after closure of the epiphyses, acromegaly develops
• In acromegaly, growth is most conspicuous in skin and soft tissues, viscera (thyroid, heart, liver, and adrenals), and the bones of the face, hands, and feet
• Bone density may increase (hyperostosis) in both the spine and the hips
• Pathophysiology of GH secretion


  1. Stimulus (exercise, aging, stress, etc.) triggers release of Growth-hormone-releasing hormone (GHRH/somatoliberin) by the hypothalamus

  2. GHRH binds to GHRH receptor on somatotroph cells in anterior pituitary

  3. Conformational change activates G-protein pathway

  
• Pathophysiology of GH action on liver


  1. GH stimulates hepatocytes by binding to GH-receptor

  2. Liver releases Insulin-growth hormone-I (IGF-I)

  3. IGF-I binds to IGF-receptor, activating multiple signaling pathways and effects

  
• Pathophysiology of GH negative feedback


  1. GH can inhibit anterior pituitary gland, decreasing GH

  2. GH stimulates somatostatin neuron to inhibit PKA, reducing GH synthesis

  3. Increased GH can directly inhibit GHRH neuron to reduce GHRH release

  
• Pathophysiology of GH action on adipose tissue

  GH binds to GH-receptor in adipose tissue, increasing lipolysis and reducing glucose uptake (catabolic)

  
• Pathophysiology of GH action on muscle


  GH increases protein synthesis and reduces glucose uptake in muscle
• Acromegaly


  Condition that develops if GH overproduction occurs in adults, after closure of epiphyses
• Gigantism


  Condition that develops if GH overproduction occurs before closure of epiphyses, allowing excessive longitudinal bone growth
• Signs and symptoms of acromegaly


  • Frontal bossing
  • Increased hand and foot size
  • Mandibular enlargement with prognathism
  • Widened space between lower incisor teeth
  • Increased heel pad thickness
  • Coarse facial features; large fleshy nose
  • Hyperhidrosis
  • Deep or hollow-sounding voice
  • Oily skin
  • Arthropathy
  • Kyphosis
  • Carpal Tunnel Syndrome
  • Proximal muscle weakness and fatigue
  • Acanthosis nigricans, & skin tags
  • Generalized visceromegaly (cardiomegaly, macroglossia, & thyroid gland enlargement)
  • Upper airway obstruction with sleep apnea
  • Diabetes mellitus
  • Increased risk of colon polyps
• Goals of acromegaly treatment


  • Control GH and IGF-1 hypersecretion
  • Ablate or arrest tumor growth
  • Ameliorate comorbidities
  • Restore mortality rates to normal
  • Preserve pituitary function

  
• Acromegaly treatment: Surgery


  1. Transsphenoidal surgical resection by experienced surgeon is preferred primary treatment

  2. Soft tissue swelling improves immediately after tumor resection

  3. GH levels return to normal within an hour

  4. IGF-1 levels are normalized within 3–4 days

  5. Acromegaly may recur in ~10% of patients several years after successful surgery

  6. Hypopituitarism develops in up to 15% of patients after surgery
• Acromegaly treatment: Somatostatin Receptor Ligands


  1. Exert therapeutic effects through SST2 and SST5 receptor subtypes expressed by GH-secreting tumors

  2. Octreotide acetate: 8-amino-acid synthetic somatostatin analogue, 40-fold greater potency than native somatostatin to suppress GH

  3. Octreotide LAR: Sustained-release, long-acting formulation that sustains GH and IGF-1 suppression for 6 weeks after injection

  4. Lanreotide: Cyclic somatostatin octapeptide analogue that controls GH hypersecretion in about two-thirds of treated patients

  5. Oral octreotide capsules (40–80 mg daily) maintain biochemical control

  
• Octreotide


  Relatively resistant to plasma degradation, 2-h serum half-life and possesses 40-fold greater potency than native somatostatin to suppress GH
• Octreotide LAR


  Sustained-release, long-acting formulation of octreotide incorporated into microspheres that sustain drug levels for several weeks after intramuscular injection
• Octreotide LAR


  • GH suppression occurs for as long as 6 weeks after a 30-mg intramuscular injection
  • Long-term monthly treatment sustains GH and IGF-1 suppression and also reduces pituitary tumor size in ~50% of patients

  
• Lanreotide


  Cyclic somatostatin octapeptide analogue that suppresses GH and IGF-1 hypersecretion after a 60-mg subcutaneous injection
• Lanreotide


  • Long-term (every 4–6 weeks) administration controls GH hypersecretion in about two-thirds of treated patients
  • Improves patient compliance because of the long interval required between drug injections
• Oral octreotide capsules


  (40–80 mg daily) maintain biochemical control in patients previously maintained on injectable formulations
• Oral octreotide capsules


  • Rapid relief of headache and soft tissue swelling occurs in ~75% of patients within days to weeks of SRL initiation
  • Most patients report symptomatic improvement, including amelioration of headache, perspiration, obstructive apnea, and cardiac failure
• Pasireotide LAR


  A multireceptor ligand with preferential SST5 binding has been shown to exhibit efficacy in achieving biochemical control in patients resistant to octreotide or lanreotide preparations
• Side effects of SRLs


  • Well tolerated in most patients
  • Adverse effects are similar for injectable octreotide and lanreotide as well as for oral octreotide formulation
  • Short-lived and mostly relate to drug-induced suppression of gastrointestinal motility and secretion
  • Occur within one-third of patients
• Symptoms of SRL side effects


  • Transient nausea
  • Abdominal discomfort
  • Fat malabsorption
  • Diarrhea
  • Flatulence
• Side effects of SRLs


  • Gallbladder contractility and emptying are attenuated
  • Up to 30% of patients develop long-term echogenic sludge or asymptomatic cholesterol gallstones
  • Mild glucose intolerance due to transient insulin suppression, asymptomatic bradycardia, hypothyroxinemia, and local injection site discomfort

  
• Pasireotide


  Associated with similar gastrointestinal side effects but with a higher prevalence of glucose intolerance and new-onset diabetes mellitus
• Pegvisomant


  Antagonizes endogenous GH action by blocking peripheral GH binding to its receptor
• Pegvisomant


  • Serum IGF-1 levels are suppressed, reducing the deleterious effects of excess endogenous GH
  • Administered by daily subcutaneous injection (10–30 mg) and normalizes IGF-1 in ~70% of patients
  • GH levels, however, remain elevated as the drug does not target the pituitary adenoma

  
• Side effects of Pegvisomant


  • Reversible liver enzyme elevation, lipodystrophy, and injection site pain
  • Tumor size should be monitored by MRI