Acromegaly

What are acromegaly and gigantism?

Acromegaly and gigantism are syndromes caused by an excess of growth hormone in the body.

  • Acromegaly occurs when this excess occurs after puberty (in adulthood)
  • Gigantism is when this excess has occurred in childhood (particularly prior to the fusion of the epiphyseal growth plates)

Here, this will mainly focus on acromegaly, as gigantism is an extremely rare condition.

Epidemiology

  • Estimated prevalence of around 40-90 cases per million population and incidence of 3-4 per million a year (i.e. rare)
  • Most common cause of mortality in these patients is cardiovascular disease
  • Growth hormone (GH) is synthesised by somatotroph cells in the anterior pituitary gland.

Physiology of Growth Hormone

o    GH release is stimulated by Growth Hormone Releasing Hormone (GHRH) and inhibited by somatostatin- both released from the hypothalamus

o    GH synthesis is regulated via a negative feedback loop pathway

  • GH inhibits somatotroph cells
    • Locally generates IGF-1 which inhibits somatotroph cell functions
    • Inhibits GHRH mRNA synthesis and GHRH release at the hypothalamus
    • Stimulates somatostatin mRNA synthesis and release at the hypothalamus.
  • Other feedback mechanisms can feed into this loop
    • e.g. ghrelin (a GI hormone released by the stomach- increases appetite)- which is thought to act in a similar fashion to GHRH to release GH
    • e.g. parasympathetic stimulation can inhibit somatostatin release (and increase GH release) – vice versa with sympathetic activation
    • e.g. glucocorticosteroids (inhibit GH secretion)

o    GH is released in a pulsatile fashion

  • Lowest in the early morning; highest during the night.  Normal (daily) levels <10ng/ml.
  • Growth Hormone circulates round the blood bound to growth hormone binding protein (50% bound) and acts on growth hormone receptors

o    Receptors mainly found in the liver, adipose tissue, heart, kidneys, intestine, lungs, pancreas, cartilage and skeletal muscle.

o    Acts to increase levels of insulin like growth factor (IGF; mainly type I- IGF1) which acts to inhibit apoptosis and stimulate cell growth and proliferations

  • Main mediator of growth during childhood
  • GH is cleared rapidly via kidneys, liver or target tissues (average half-life 10-20 mins)
  • Majority of cases are secondary to somatotroph adenomas (mostly macroadenomas).  Other, extremely rare, causes include GHRH hypothalamic tumours and ectopic production of GH/GHRH from neuroendocrine tumours.
  • Excess GH/IGF-1 has effects on multiple systems: mainly increasing size

Pathophysiology of Acromegaly

o    Cardiovascular system

  • Acromegaly-associated cardiomyopathy: a biventricular concentric hypertrophy
  • ‘hyperkinetic syndrome’- early feature of increased cardiac contractility, high cardiac output and lowered peripheral resistance. Later, fibrosis occurs and both diastolic filling and systolic function is impaired
    • When this is combined with hypertension and/or associated valvular disease, this can cause features of heart failure
  • Patients also can develop Hypertension (common), coronary artery disease and they are at much higher risk of arrhythmias

o    Respiratory System

  • The main respiratory problem that patients present with is sleep apnoea due to swelling/collapse of the pharyngeal walls secondary to GH excess
  • Other problems include growth/thickening of various components of the upper and lower respiratory tracts
    • Upper: e.g. swelling/lengthening of the soft palate; thickening of the true and false vocal folds (deep voice)
    • Lower: e.g. increased lung volume and compliance; small airway narrowing; elongation of ribs/spine kyphosis

o    Musculoskeletal system

  • Arthropathy of both the peripheral and axial skeleton- joint space narrowing (after initial widening), osteophyte formation and other features of osteoarthritis.  Hip and shoulder are common sites.

o    Endocrine/Metabolic systems

  • Diabetes mellitus or impaired glucose tolerance is common in patients with acromegaly.  Hypertriglyceridaemia is also seen.
  • Thought to be due to the effects of IGF-1 on insulin sensitivity.

Clinical Features of Acromegaly

o    Tumour effects: e.g. visual field defects ((bi)temporal hemianopia); cranial nerve palsy; headache

o    May be other features of other pituitary hormone excess/deficiency e.g. galactorrhoea, decreased libido, menstrual abnormalities

o    Musculoskeletal/Skin: Enlargement of the soft tissues, particularly hands and feet; Prognathism (protrusion/prominence of the jawbone); arthralgia/arthritis; carpal tunnel/other nerve entrapment syndromes; proximal myopathy; frontal bone hypertrophy; oily skin; skin tags; facial appearance is said to become ‘more hoarse’

o    Respiratory: Sleep problems (apnoea)- tiredness, snoring etc; deepening voice

o    Cardiovascular: Could present with angina or features of cardiac failure (although this would generally develop quite late); more likely to be picked up as raised BP

o    Visceromegaly: Tongue; thyroid/salivary gland; liver; spleen; kidney; prostate

o    Endocrine: Diabetes mellitus

Investigations

o    Oral glucose tolerance test– the patient is fasted overnight, comes to clinic in the morning and blood test is taken (for fasting glucose and GH).  The patient drinks a glucose solution (75g) and further blood tests are taken at 30 min intervals for 2 hours.

o    Normally, GH levels will fall below baseline levels with the glucose test.  If there is too much GH (acromegaly), this will not occur.

o    Other tests you may want to carry out (depending on the patient) include:

o    Other pituitary hormone tests

  • Insulin stress test for cortisol and GH
  • TRH test for TSH response
  • LHRH test for LH/FSH response

o    MRI brain (CT chest and abdo if this is negative to look for ectopic production sites)

o    Bloods

  • Glucose (you may also want to test fasting glucose for diabetes)

o    Echocardiogram

Management

o    Surgery

o    Indicated for most cases (pituitary micro/macroadenomas).  Trans-sphenoidal approach is commonly used.

  • Reported up to 10% recur (most likely growth of residual tumour) and up to 30% have subsequent hypopituitarism.

o    Radiotherapy

o    Drug-treatment (indicated after surgery if total debulking was not possible/if symptoms remain)

o    Somatostatin receptor ligands e.g. Octreotide and Lanreotide

  • Selective somatostatin receptor SST2/SST5 ligands (expressed mainly by somatotroph cells).
  • Effectiveness is determined by initial levels of GH
  • Shrinkage of tumour occurs in 50% but reverses with cessation of treatment.  More than 80% have a reduction in symptoms.
  • Main side-effects include nausea, vomiting, loose/oily stools, constipation, stomach upset, gas, bloating, dizziness or headaches.

o    GH-receptor antagonists e.g. Pegvisomant

  • Used in patients intolerant to somatostatin analogues without central compressive symptoms and patients with severe diabetes (shown to improve insulin sensitivity)
    • IGF-1 used as a marker of success of treatment
  • Expensive

o    Dopamine Receptor Agonists e.g. Bromocryptine, Cabergoline

  • High doses can potentially induce a reduction of GH levels to baseline
  • Particularly useful where somatostatin analogues have failed; or where there is co-existent hyperprolactinaemia

Monitoring

o    Annual biochemical testing for GH/IGF-1 and annual pituitary MRI if on medical treatment.  If complete resection and resolution of symptoms, then annual monitoring may only be required in the short term.

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