A 25-Year-Old Woman with Headache and Joint Pain

Fig. 8.1

Pre-operative MRI pituitary. Pre-contrast T1 weighted images in the coronal (a) and sagittal (b) plain show a homogenous mass arising from the pituitary fossa and invading the left cavernous sinus (arrow). The tumour extends into the suprasellar cistern. It encroaches upon but does not compress the optic chaism (arrowhead)

MRI shows a homogenous pituitary macroadenoma measuring 2 cm in craniocaudal diameter. It extends into the suprasellar cistern but does not compress the optic chiasm. The tumour invades the left cavernous sinus.

What is the diagnosis?

Acromegaly due to a GH secreting pituitary tumour (somatotroph adenoma). The raised prolactin level may be due to pituitary stalk distortion or co-secretion of prolactin from the tumour (somatomammotroph adenoma).

What treatment would you recommend?

Surgical resection: This is the primary treatment for most patients. Rates of postoperative remission are dependent on the tumour size and the experience of the surgeon. Tumours which invade the cavernous sinus are difficult to completely resected due to the risk of bleeding from the highly vascular sinus.

Pre-operative somatostatin analogue (SSA) treatment (see below) may be beneficial in reducing soft tissue swelling and reduce the risk of anaesthetic complications in patients with severe macroglossia and enlarged laryngeal tissues. In the case of very large tumours, pre-operative SSA may also improve the surgical outcome and increase the likelihood of post-operative remission. However, this is controversial and the results of prospective clinical trials evaluating this approach are awaited.

The patient undergoes transsphenoidal surgery to debulk the pituitary tumour. Histological analysis confirms a pituitary adenoma with a low ki-67 index (proliferative index) of less than 1 %. Immunohistochemical staining is weakly positive for GH and negative for all other anterior pituitary hormone. This suggest a sparsely granulated somatotroph adenoma which could be confirmed with electron microscopy.

Post-operative testing shows that her GH and IGF-1 levels have declined but remain elevated. The remainder of her pituitary function is preserved.

What are the treatment options now?

Medical

SSA are the most commonly used medical therapy for acromegaly. They have both anti-tumour and anti-secretory effects on somatotroph adenomas. Long-acting formulations are usually administered monthly by intramuscular injection. This treatment will normalise IGF-1 in approximately 60 % of patients. Tumour shrinkage is less predictable but up to 80 % of patients are reported to display at least 20 % tumour volume reduction. Sparsely granulated tumours may be more resistant to SSA therapy.

Pegvisomant prevents GH binding to its receptor and producing IGF-1. This drug can normalise IGF-1 in the majority of patients with acromegaly, if used in sufficient doses. Serum GH levels rise during therapy and the drug cross reacts with many GH assays. Therefore, serum GH levels should not be measured while taking pegvisomant, but IGF-1 concentration should be used to titrate the appropriate dose. It is administered daily (or on alternate days) by deep subcutaneous injection.

Dopamine agonists can also lower GH levels and may cause modest tumour shrinkage. They are administered orally. A higher weekly dose, than used in prolactinoma, is often required for clinical effectiveness.

Radiotherapy

External beam radiotherapy is a long-established and effective treatment of acromegaly. Treatment results in stabilisation of tumour size more commonly than shrinkage. GH levels decline slowly and it may take 10 years for the maximal biochemical effect to be seen. Radiotherapy may damage the normal pituitary gland resulting in hypopituitarism in 50 % of treated subjects after 10 years. This may have significant implications for young patients who wish to preserve fertility.

The patient is planning to start a family; therefore, it is decided to use medical therapy to control acromegaly for now.

What side effects may be encountered with medical therapy for acromegaly?

SSA can cause nausea and diarrhoea. Gallstones commonly develop when using long term SSA. However, these are typically asymptomatic unless the drug is stopped suddenly.

Dopamine agonists can cause nausea, postural hypotension, constipation and rarely psychological symptoms such as depression or impulse control disorders. Also, they occasionally induce Raynaud’s phenomenon. Long-term use of high-dose dopamine agonist in Parkinson’s disease has been associated with valvular heart disease. However, it is controversial whether this risk applies to patients with patients with pituitary tumours.

Pegvisomant can cause derangement of liver biochemistry in 2–3 % of patients. This should be monitored regularly, particularly with concurrent use of SSA. It normally improves with dose reduction or discontinuation. Initial concerns about enlargement of the tumour remnant while taking pegvisomant have not been borne out with clinical experience.

The patient is commenced on a long-acting somatostatin analogue. Her GH and IGF-1 decline further but she continues to have active acromegaly.

Can combinations of medical treatment be used?

There is increasing experience with the use of combination medical therapy in acromegaly. SSA and pegvisomant or SSA and cabergoline are the most commonly used combinations. This appears safe and effective but derangement of liver biochemistry is more common with the former combination. This may necessitate dose reduction or cessation of some medications.

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