Acromegaly

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

enclosed pituitary tumour

1st line – transsphenoidal surgery

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1st line –

transsphenoidal surgery

Indicated as a primary treatment approach in cases of enclosed somatotroph microadenomas (<10 mm diameter) and macroadenomas (>10 mm diameter).

Surgical remission rates in centres with experienced neurosurgeons are between 80% and 90% of microadenomas and between 50% and 75% of macroadenomas.[13]

Complications of transsphenoidal surgery include local complications (cerebrospinal fluid leak, meningitis, haemorrhage): 5%; diabetes insipidus: 1% to 5%; hypopituitarism: 10%.

2nd line – somatostatin analogue (SSA)

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2nd line –

somatostatin analogue (SSA)

If surgery fails to achieve remission of acromegaly, SSAs (also known as somatostatin receptor ligands) are the indicated medical treatment.[13][31]

First-generation SSAs include octreotide (available in oral, subcutaneous, or intramuscular depot formulations) and lanreotide (available as a subcutaneous depot formulation). The second-generation SSA, pasireotide, has an enhanced affinity for the SST-5 receptors. It is indicated in patients who have an inadequate response to surgery and is also effective in patients whose disease is not fully controlled on first-generation SSAs.

In terms of efficacy, first-generation SSAs have shown biochemical remission (around 40% of patients), improvement of symptoms, and tumour volume reduction (over 60% of patients).[31]

Long-acting preparations of octreotide and lanreotide appear to have a similar degree of efficacy in terms of leading to clinical improvement and biochemical control of the disease.[32] The subcutaneous preparation of rapid-acting, aqueous octreotide is sometimes recommended for headache improvement.

Oral octreotide is approved for the treatment of acromegaly in patients who are controlled on injectable SSAs.[33] In one study, the long-term maintenance of response in patients on oral octreotide was 90%.[34]

Pasireotide was found to be effective in normalising plasma IGF-1 concentration in approximately 50% more patients than long-acting octreotide.[35] A common adverse effect of pasireotide is an increase in the incidence of hyperglycaemia or diabetes mellitus.[39][40] Predictive factors for hyperglycaemia are high baseline glucose, history of hypertension, and dyslipidaemia.[41] Octreotide and lanreotide have a neutral effect on glucose control.[26]

Combination treatment of an SSA (either first- or second-generation) and pegvisomant can be considered in certain patients.[47]

Primary options

octreotide: 50 micrograms subcutaneously three times daily initially, adjust dose according to response, maximum 1500 micrograms/day; 20 mg intramuscularly (long-acting depot) every 4 weeks for 3 months initially, adjust dose according to response, maximum 40 mg every 4 weeks; 20 mg orally twice daily initially, adjust dose according to response, maximum 80 mg/day

Adjust dose according to clinical response, growth hormone level, and serum insulin-like growth factor 1 (IGF-1) level (every 2 weeks for subcutaneous and oral formulations). The intramuscular depot formulation is only recommended for patients who have responded to, and tolerated, subcutaneous octreotide. The oral formulation is only recommended for patients who have responded to, and tolerated, parenteral octreotide or lanreotide.

lanreotide: 90 mg subcutaneously (long-acting depot) every 4 weeks for 3 months initially, adjust dose according to response, maximum 120 mg every 6-8 weeks

pasireotide: 40 mg intramuscularly (long-acting depot) every 4 weeks for 3 months initially, adjust dose according to response, maximum 60 mg every 4 weeks

Consider – dopamine agonist

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Consider –

dopamine agonist

Additional treatment recommended for SOME patients in selected patient group

Cabergoline, a second-generation dopamine agonist, is considered in patients with moderate elevations of insulin-like growth factor 1 (IGF-1) (<2.5 the upper normal limit for age) postoperatively or as add-on therapy in patients who do not achieve biochemical control with maximal doses of somatostatin analog (also known as somatostatin receptor ligand) treatment.[13]

Primary options

cabergoline: 0.25 mg orally twice weekly initially, increase by 0.25 mg twice weekly increments every 4 weeks according to response, maximum 4 mg/week

2nd line – growth hormone-receptor antagonist (GHRA)

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2nd line –

growth hormone-receptor antagonist (GHRA)

GHRA treatment may be considered in patients who have not responded adequately to surgery, radiotherapy, or somatostatin analogues, or when these therapies are unsuitable or not tolerated.[42] The only available GHRA is pegvisomant, a recombinant human GH analogue that has been structurally altered to act as a GH antagonist.

It is used as adjuvant therapy following surgery, as monotherapy, or in combination with other medical therapies.[12][13] Pegvisomant can also be used as an equal line treatment to SSAs in certain patients.

Pegvisomant therapy has a high efficacy in the biochemical control of acromegaly with insulin-like growth factor 1 (IGF-1) normalisation in about 73% of patients, but it does not induce tumour shrinkage.[24]

In patients with diabetes mellitus pegvisomant treatment improves glucose metabolism.[26]

Primary options

pegvisomant: 40 mg subcutaneously as a loading dose, followed by 10 mg subcutaneously once daily, then increase by 5 mg increments every 4-6 weeks according to response and serum IGF-1 levels, maximum 30 mg/day

3rd line – radiotherapy

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3rd line –

radiotherapy

Radiotherapy is indicated for patients with aggressive adenomas uncured by surgery and resistant to medical treatment, or patients who are unfit for, or declined surgical and/or medical therapy.[13] Stereotactic radiotherapy, such as a single dose (gamma knife radiosurgery) or delivered as a small number of fractions, is suggested over conventional radiotherapy in patients with acromegaly, unless there is significant residual tumour burden, or if the tumour is too close to the optic chiasm.[12] The most common complication after the administration of radiotherapy (regardless of type) is hypopituitarism, which develops slowly over time in parallel with the achievement of control over GH and IGF-I levels.[43] Hypopituitarism levels appear to be lower with stereotactic radiosurgery (SRS); however, the reported mean follow-up for those undergoing SRS is shorter than the follow-up period documented for fractionated radiation.[44][45]

unresectable pituitary tumour (with neural or vascular impingement/invasion)

1st line – somatostatin analogue (SSA)

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1st line –

somatostatin analogue (SSA)

In cases of tumours (macroadenomas) unlikely to be completely resected (those invading a cavernous sinus or the sella turcica floor) medical therapy with SSAs (also known as somatostatin receptor ligands) may be indicated.[31] However, even partial tumour debulking leading to a substantial decline of growth hormone (GH) concentrations improves the efficacy of subsequent drug therapy and radiation modalities.[30]

In terms of efficacy, first-generation SSAs have shown biochemical remission (around 40% of patients), improvement of symptoms, and tumour volume reduction (over 60% of patients).[31]

Oral octreotide is approved for the treatment of acromegaly in patients who are controlled on injectable SSAs.[33] An oral capsule of octreotide has been shown to facilitate intestinal absorption of octreotide by its novel transient permeability enhancer formulation. In one study, the long-term maintenance of response in patients on oral octreotide was 90%.[34]

Combination treatment of an SSA (either first-or second-generation) and pegvisomant can be considered in certain patients.[47]

Primary options

lanreotide: 90 mg subcutaneously (long-acting depot) every 4 weeks for 3 months initially, adjust dose according to response, maximum 120 mg every 6-8 weeks

pasireotide: 40 mg intramuscularly (long-acting depot) every 4 weeks for 3 months initially, adjust dose according to response, maximum 60 mg every 4 weeks

Consider – dopamine agonist

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Consider –

dopamine agonist

Additional treatment recommended for SOME patients in selected patient group

Primary options

cabergoline: 0.25 mg orally twice weekly initially, increase by 0.25 mg twice weekly increments every 4 weeks according to response, maximum 4mg/week

Consider – debulking surgery

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Consider –

debulking surgery

Additional treatment recommended for SOME patients in selected patient group

For tumours (macroadenomas) unlikely to be completely resected, debulking surgery is indicated in cases with compression of neural structures, such as optic tracts. It may also aid biochemical control when combined with adjuvant medical or radiotherapy.[30]

2nd line – growth hormone-receptor antagonist (GHRA)

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2nd line –

growth hormone-receptor antagonist (GHRA)

Pegvisomant therapy has a high efficacy in the biochemical control of acromegaly with insulin-like growth factor 1 (IGF-1) normalisation in about 73% but it does not induce tumour shrinkage.[24]

In patients with diabetes mellitus pegvisomant treatment improves glucose metabolism.[26]

Primary options

3rd line – radiotherapy

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3rd line –

radiotherapy

Radiotherapy is indicated for patients with aggressive adenomas uncured by surgery and resistant to medical treatment, or patients who are unfit for, or declined surgical and/or medical therapy.[13] Stereotactic radiotherapy, such as a single dose (gamma knife) or delivered as a small number of fractions, is suggested over conventional radiotherapy in patients with acromegaly, unless there is significant residual tumour burden, or if the tumour is too close to the optic chiasm.[12] The most common complication after the administration of radiotherapy (regardless of type) is hypopituitarism, which develops slowly over time in parallel with the achievement of control over GH and IGF-I levels.[43] Hypopituitarism levels appear to be lower with stereotactic radiosurgery (SRS); however, the reported mean follow-up for those undergoing SRS is shorter than the follow-up period documented for fractionated radiation.[44][45]

non-pituitary adenoma aetiology

1st line – medical and surgical interventions

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1st line –

medical and surgical interventions

In rare cases where acromegaly results from ectopic production (e.g., hypothalamic, bronchial, pancreatic, adrenal tumours) of growth hormone (GH) or GH-releasing hormone, treatment consists of medical (somatostatin analogue) and surgical interventions (tumour resection) to address the specific lesion (e.g., bronchial carcinoid, pancreatic islet cell tumour).

ONGOING

pituitary adenoma progression or recurrence

1st line – repeat surgery

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1st line –

repeat surgery

Repeat pituitary surgery (either debulking surgery or tumour mass removal depending on tumour characteristics) may be indicated for patients who fail to benefit (i.e., improved biochemical measures, reduced tumour size) from initial surgical (adenoma resection or debulking), medical, and radiotherapy interventions, but its efficacy is usually lower than that of the first intervention.[48]

2nd line – repeat radiation

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2nd line –

repeat radiation

Repeat stereotactic radiosurgery may further increase delayed radiation-related complications. However, some patients have an enlarging tumour despite previous surgery and radiation and medical treatment and need additional therapy, including radiation. One large multi-institutional series showed that repeat gamma knife radiosurgery for patients with acromegaly was well tolerated, with 81.0% of patients reporting no radiosurgery-induced toxicity.[46] All reported toxicities were related to endocrine or cranial nerve dysfunction. The endocrine control rate was 42.9%, with a median follow-up of 3.8 years and tumour control 83.3%.

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Acromegaly

Treatment algorithm

enclosed pituitary tumour

transsphenoidal surgery

somatostatin analogue (SSA)

Primary options

dopamine agonist

Primary options

growth hormone-receptor antagonist (GHRA)

Primary options

radiotherapy

unresectable pituitary tumour (with neural or vascular impingement/invasion)

somatostatin analogue (SSA)

Primary options

dopamine agonist

Primary options

debulking surgery

growth hormone-receptor antagonist (GHRA)

Primary options

radiotherapy

non-pituitary adenoma aetiology

medical and surgical interventions

pituitary adenoma progression or recurrence

repeat surgery

repeat radiation