Acromegaly

Acromegaly is one of the functional pituitary diseases.  It is a condition caused by the persistent hypersecrection of growth hormone. 


Overview

The annual incidence of this condition in the USA of approximately three to four million people, but this is probably an underestimate since it is fairly difficult to diagnose this condition early. Excessive growth hormone stimulates the liver to secrete insulin like growth factor I (IGF-1). IGF-1 causes the symptoms and signs of acromegaly.  

houston acromegaly
Notable cases of acromegaly

Abraham Lincoln, the 16th president of the USA, seemed to have acromegaly based on photographs. "Andre the Giant" (Andre Rene Roussimoff), wrestler and actor, 7'4" passed away at the at of 46 after choosing not to be treated for the disease. Actor Richard Kiel from James Bond movies and Mr. Larson in the movie Happy Gilmore is also known to have this condition.   

Diagnosis

The diagnosis is based on a two step process. First, bio-chemical evidence (blood testing) of growth hormone excess needs to be shown. The measurement of growth hormone and age-matched IGF-1 (insulin like growth factor 1) concentrations are the most import biochemical variables for the diagnosis and eventual monitoring. 
1. Measure screening age-match IGF-1 levels. If elevated then consider a growth hormone suppression test. If normal, then acromegaly is very unlikely.
2. Confirm the diagnosis with a oral glucose tolerance test (OGTT) for growth hormone.  
Once the condition is diagnosed by blood work, then imaging tests are ordered to locate the source of the growth hormone. Most commonly the growth hormone excess is coming from a pituitary tumor

Natural history of the disease

Normally the body does not require high levels of growth hormone after puberty. Growth hormone excess by definition will cause organs to grow. In adults, since bone growth plates have already fused, the excess growth hormone will cause excessive growth of soft tissues and muscles. 

Both morbidity and mortality rates are higher in uncontrolled acromegaly. This poor outcome is directly related to the effect of raised growth hormone and IGF-1 levels. The major diseases associated with acromegaly are heart disease, diabetes mellitus, high blood pressure, sleep apnea, arthritis, and osteoporosis. All these conditions can be improved, although only partial regression may be achieved, with normalization of growth hormone levels. Patients with colonic polyps should be followed according to national guidelines for colon cancer. Loss of peripheral vision can be a symptoms in patients whose pituitary mass is large. 

Treatment

Role of neurosurgery- 
Complete surgical removal of the growth hormone secreting tumor results in hormonal control of acromegaly and possible regression of some soft tissue changes. Transsphendoidal surgery is the treatment of choice for pituitary tumors (microadenomas and microadenomas) that are within the sella  and when the tumor is causing compression symptoms. In patients with intrasellar microadenomas, surgical removal can usually give biochemical control in 75-95% of patients. Control rates are lower in patients with macroadenomas (40-70%). Contraindications to surgery are patient refusal, severe heart or lung disease, or the lack of an available skilled surgeon. 

Role of medical therapy

There are three drug classes available for the treatment of acromegaly. A board certified endocrinologist such as Dr Fareed Elhaj and Dr. Medhavi Jogi should be involved in the mangement of a patient with acromegaly. If medical therapy is needed, it is generally needed lifelong.
 
Somatostatin receptor ligands (SRL) 
These injectable drugs lead to decreased in the tumor growth hormone secretion. They can be used as a first line therapy when there is a low probability of surgical cure. The drugs are most commonly used after surgery has failed to achieve biochemical control. Common side effects include abdominal bloating, cramping, gallstones, and rarely pancreatitis. Patients should remain on doses for approximately 3-6 months at a time to assess adequacy of treatment or dose titration.

Growth Hormone antagonists (GHRA) 
There is currently only one injectable drug of this class available called pegvisomant. The indications for its use are in patients that have persistently elevated IGF-1 levels despite max therapy with other treatments, or possible first line therapy.  Safety issues with this class of medications include transient liver function abnormalities (25%) and tumor growth which is infrequent (<2%). Combination of GHRA and SRL may be useful for patients with disease that is resistant to one or the other treatment. 

Dopamine agonists (DA)
Bromocriptine and cabergoline are the only two drugs in this class. Only cabergoline has any effectiveness in the treament of acromegaly. Monotherapy with this medication is effective in less than 10% of patients. The drug can be considered in patients that only want an oral medication and in patients who have concurrently high prolactin levels. 


Role of radiation therapy

Radiation therapy should generally be considered in patients as a third line therapy when surgery and medical therapy have failed. There are many side effects of radiation therapy but the main risks are destruction of all pituitary function (panhypopituitarism) and vision loss (<5%).


Monitoring

During followup after neurosurgery or radiotherapy a controlled growth hormone level can be defined as growth hormone suppression during an OGTT and a normal IGF-1 level 3-6 months after surgical intervention. Patients that require somatostatin receptor ligand treatment or dopamine agonist treatments, the goal is to monitor random IGF-1 and random growth hormones. An OGTT may not be helpful for monitoring response in patients on active medical therapy. In patients on GH receptor antagonists, only the IGF-1 level should be followed. 

 Outcome     Criteria Usual management
 Active disease Random GH >1 ug/L
OGTT-GH not suppressed
High IGF-1
 Periodic MRI
Treat comorbidities
Actively treat or change treatment
 Controlled Disease Random GH <1 ug/L
Suppression of OGTT-GH
Normalized IGF-1
Periodic MRI q2-3yr
No change in treatment or reduction in doses

References
Consensus criteria for cure. J Clin Endocrinol Metab, July 2010, 95(7):3141–3148
Guideline for acromegaly management: an update. J Clin Endocrinol Metab, May 2009, 94(5):1509–1517
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