Acromegaly

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

The goals of treatment of acromegaly are to:[24]

Restore life expectancy to normal
Relieve symptoms of the condition
Completely remove the causative tumour, if possible; if not possible, control its growth and related mass effects
Preserve normal pituitary functioning
Improve quality of life

Reduction or elimination of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) hypersecretion can lead to reversal of many of the comorbidities associated with acromegaly. Treatment options include surgery, pharmacological treatment, and radiotherapy.

Remission of acromegaly is defined by biochemical control:[13]

Age- and sex-matched plasma IGF-1 reduced to normal levels
Nadir GH after oral glucose tolerance test <0.4 or 1 microgram/L (<1 nanogram/mL), depending on assay used.

The markers of biochemical control shown to influence mortality are the serum GH and IGF-1 levels at last follow-up.[25] Treatment of acromegaly should aim for serum GH <0.4 or 1 microgram/L (<0.4 or 1 nanogram/mL) (as measured by modern sensitive immunoassays) and normal serum IGF-1 values, to restore the elevated mortality of the condition to normal levels.[26][27]

Complications of acromegaly include cardiovascular, endocrine, metabolic, and oncological comorbidities; sleep apnoea; and bone and joint disorders.[26] Comorbidities and mortality associated with acromegaly differed by sex in a Korean population and more research is needed to elucidate causes.[28] Currently, in most studies, mortality seems to be similar to the general population in adequately treated patients with acromegaly.[27]

Transsphenoidal and debulking surgery

Transsphenoidal surgery is 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]

Positive GH immunostaining in surgical specimens in patients with suspected acromegaly confirms the diagnosis of a pituitary GH-secreting adenoma. On the basis of the number of cytoplasmic granules, somatotroph adenomas are divided into densely and sparsely granulated types, with the latter type indicating a more aggressive tumour.[29]

Complications of transsphenoidal surgery include:[4]

Local complications (cerebrospinal fluid leak): 2% to 3%
Diabetes insipidus: 8% to 9%
Hypopituitarism: 6% to 7%

Debulking surgery is indicated for those with tumours that are unlikely to be completely resected (those in close proximity with neural structures [e.g., optic tracts] or those invading a cavernous sinus or the sella turcica floor) when neural structure compression is present. It may also aid biochemical control when combined with adjuvant medical or radiotherapy.[30]

Somatostatin analogues (SSAs)

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

Primary therapy with SSAs is considered in patients with probability of poor surgical remission rate (patients with large and invasive adenomas and without compression signs), those with comorbidities enhancing surgical risk, and those who decline surgery.[13][31]

First-generation SSAs include octreotide (available in oral, subcutaneous, or intramuscular depot formulations) and lanreotide (available as a subcutaneous depot formulation), which primarily bind to somatostatin receptor sub-type 2 (SSTR2) and with less affinity to SSTR5. These treatments require lifelong administration and are relatively costly.

The efficacy of first-generation SSAs in the treatment of acromegaly is assessed mainly by evaluation of biochemical markers, but also by symptom improvement and tumour volume reduction. In these regards, SSAs have shown the following results:[31]

Biochemical remission: around 40% of patients
Improvement of symptoms
Tumour volume reduction: over 60% of patients

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 recommended for headache control.

After initial dosing is established, the SSA dose is titrated after 3 to 4 months to achieve biochemical control. Gallstones or biliary sludge (up to 25% of cases) and mild to moderate hyperglycaemia (in 10% to 15% of cases) are common adverse effects of both of these medicines.

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]

Pasireotide is a second-generation SSA with enhanced affinity for the SST-5 receptors. It appears to have higher efficacy in normalising GH and IGF-1 concentrations compared with octreotide in patients with acromegaly. In one study, a long-acting release formulation was found to be effective in normalising plasma IGF-1 concentration in approximately 50% more patients than long-acting octreotide.[35] Pasireotide is approved for the treatment of acromegaly in patients who have had an inadequate response to surgery or for those in whom surgery is not an option.[36] It is also effective in patients whose disease is not fully controlled on first-generation SSAs and has been shown to decrease GH and IGF-1 in approximately 25% of patients resistant to long-acting octreotide or lanreotide.[37][38] 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] Otherwise, the side-effect profile of pasireotide is similar to that of the older SSAs.

Dopamine agonists

Historically bromocriptine was used, but is no longer recommended because IGF-1 was normalised in only 10% of patients. Cabergoline, a second-generation dopamine agonist, is considered in patients with moderate elevations of IGF-1 (<2.5 the upper normal limit for age) persist postoperatively or as add-on therapy in patients who do not achieve biochemical control with maximal doses of SSA treatment.[13]

GH-receptor antagonist (GHRA)

The only available GHRA is pegvisomant, a recombinant human GH analogue that has been structurally altered to act as a GH antagonist. Pegvisomant may be considered in patients who have not responded adequately to surgery, radiotherapy, or SSAs, or when these therapies are unsuitable or not tolerated.[42] It is used as adjuvant therapy following surgery, as monotherapy, or in combination with other medical therapies.[12][13] Pegvisomant therapy has a high efficacy in the biochemical control of acromegaly with IGF-1 normalisation in about 73% of patients.[24] Tumour growth has been noted in around 7% of patients.[24] Liver function test abnormalities (elevated transaminases) may occur, possibly due to idiosyncratic drug toxicity.

Patients with diabetes mellitus

The presence of diabetes mellitus influences the choice of acromegaly medical therapy: octreotide and lanreotide have a neutral effect on glucose control; pasireotide has a high-risk for developing hyperglycaemia in patients with uncontrolled diabetes; pegvisomant treatment improves glucose metabolism.[26]

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, which may be 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 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]

Pituitary adenoma progression or recurrence

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

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%.

Non-pituitary adenoma aetiology

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

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