By Daniel F. Kelly, MD, Garni Barkhoudarian, MD, Pejman Cohan, MD, and Sharmyn McGraw
This article on acromegaly is the second in a series of regular blogs on the diagnosis and treatment of pituitary adenomas and related hormonal disorders. Here we provide a brief overview of acromegaly, its manifestations and the optimal management including both surgical and medical advances. We’ve added links to helpful resources including relevant articles written by others as well as by our Pacific Pituitary Disorders Center team.
In almost all cases, acromegaly is caused by a benign (non-cancerous) tumor of the pituitary gland (also known as the master gland) that secretes excess growth hormone (GH). The elevated blood GH levels cause the liver in turn to make excess insulin-like growth factor-1 (IGF-1), a hormone that has wide effects throughout the body. In patients with acromegaly, the elevated GH & IGF-1 levels can lead to numerous problems, many of which are manifested in one’s appearance and body habitus. These changes include enlargement of the hands and feet, enlargement and protrusion of the forehead (frontal bossing) and jaw (prognathism), temporomandibular (TMJ) syndrome, spreading of the teeth, increased facial hair in woman, as well as excessive sweating of the palms (hyperhidrosis). Excess body fluid and tissue thickening can occur in the tongue and throat area– leading to snoring and obstructive sleep apnea–and in the hands leading to carpel tunnel syndrome. Even more serious for long term health is the increased risk of heart enlargement (cardiomegaly and cardiomyopathy), hypertension and diabetes as well as increased risk of colon polyps and colon cancer. Over time, untreated acromegaly results in an increased risk of death mostly related to associated cardiovascular disease and diabetes. For patients with larger pituitary tumors (typically over 1.5 cm in diameter), there may be symptoms of visual loss from pressure on the optic nerves and optic chiasm, headaches and symptoms of pituitary gland failure (hypopituitarism) including low energy, low libido, loss of menstrual periods in women and weight gain.
While often described as a rare disorder, “relatively uncommon” may be a more apt descriptor of acromegaly. The disorder occurs fairly equally between men and women and can occur at any age but is more common in adulthood. If a child or adolescent develops a GH-secreting pituitary adenoma before their bones are fused, gigantism will develop. Gigantism is associated with excessive height, with many “pituitary giants” growing to over 7 or 8 feet in height.
The good news is that once pituitary-related acromegaly or gigantism is diagnosed, endonasal tumor removal of the pituitary tumor performed by experienced pituitary surgeons, has a very high success rate and safety record. Overall, 70-80% of patients with acromegaly achieve remission with surgery, and the resultant normalized GH and IGF-1 levels lead to resolution of many of the associated problems of the disease such as hypertension, diabetes, carpal tunnel syndrome, snoring and sleep apnea. If surgery is not initially successful, use of medications is typically successful, and for the minority of patients who do not achieve remission with combination of surgery and medications, stereotactic radiosurgery (focused radiation) can lead to remission in the great majority of patients. These therapies need to be carefully considered, ideally in a multidisciplinary setting with a team of pituitary specialists, including neurosurgeons and endocrinologists.
The two major challenges in acromegaly are:
1. Establishing a diagnosis
2. Effectively removing the adenoma and normalizing GH and IGF-1 levels
We treat many patients with acromegaly who, in retrospect, had been having symptoms or signs of the disorder for years. Most commonly, these patients (or their significant others) notice their shoe size or ring size gradually increasing, increased snoring, or new skin tags on the back and torso. Some patients may also have been recently diagnosed with hypertension and/or diabetes. Finally, others might also complain of symptoms resulting from progressive tumor enlargement leading to pituitary gland failure and optic nerve compression — such as increasing fatigue and decreased libido, as well as headaches and visual loss. Pituitary-related headaches are typically seen with large tumors and are generally localized to the forehead region or top of the head. Pituitary-related loss of vision typically manifests as decreased peripheral visual fields (aka bitemporal hemianopsia) and visual acuity.
Once the clinical suspicion of acromegaly has been raised, confirming the diagnosis is determined by blood testing of GH and IGF-1 levels, both of which will generally be elevated, although in some instances, GH levels drawn at random times of the day may be “normal”. As a result, in the setting of a normal GH level but elevated IGF-1 level, many endocrinologists will also perform an oral glucose tolerance test. During this test, an oral glucose drink is given, after which blood samples for GH are taken every 30 minutes for 2 hours. In normal individuals, GH levels suppress to very low levels, whereas in patients with acromegaly, the GH levels will not suppress after glucose intake. Following hormonal testing that confirms acromegaly, all the other pituitary hormones should be tested and an MRI of the pituitary with gadolinium contrast should be performed to confirm the presence of a pituitary adenoma. In the vast majority of individuals, an adenoma will be seen, typically a macroadenoma (larger than 1 cm in diameter). For patients with visual complaints or a macroadenoma resulting in optic chiasm contact or compression on MRI, formal visual field testing by an ophthalmologist or neuro-ophthalmologist should also be performed.
“The diagnosis of acromegaly came as quite a shock. Walking into Dr. Pejman Cohan’s office wondering why my cholesterol was high and I couldn’t lose weight in spite of a healthy diet. I never dreamed my doctor would tell me he suspected I had a pituitary tumor causing too much growth hormone. Dr. Cohan noticed the most subtle indications in my hands and facial features which lead to a very timely diagnosis and I am so grateful. Dr. Cohan soon introduced me to Dr. Kelly and his wonderful team at the Pacific Pituitary Disorders Center and I am now celebrating over eight years of remission with excellent health. I feel fortunate to have this team of experts in my own back yard. Thank you, thank you, thank you!”
– Shady F.
First-line treatment of acromegaly – Endonasal Surgery:
Fortunately, there are excellent treatments for acromegaly, starting with surgery, then medical therapies and lastly, focused radiation or radiosurgery. After diagnostic confirmation of acromegaly, endonasal transsphenoidal adenoma removal is considered first-line treatment. When performed by an experienced pituitary surgery team, long-term remission rates average 70- 80% and the risk of major surgical complications is very low, including a risk of new pituitary gland failure of less than 5%. The success rates are highest (typically greater than 85%) in patients with clearly defined non-invasive microadenomas (less than 1 cm in diameter) as seen on MRI. For patients with invasive adenomas, adenomas greater than 2 cm in diameter, or those with markedly elevated GH and IGF-1 levels, remission rates are substantially lower (typically ranging from 40-60%).
While we perform all of our pituitary operations using an endonasal endoscopic approach, studies to date have not been able to confirm that a purely endoscopic approach is better than a traditional microscopic approach (see Starke et al 2013). However, several studies including our own (see McLaughlin et al 2013) have shown the benefit and advantage of endoscopy for maximizing tumor removal, especially for larger tumors over 2 cm in diameter. Given that it is known that a greater percentage of GH-secreting tumor removal correlates with a higher likelihood of success with medical therapy in patients with acromegaly, we strongly recommend use of a fully endoscopic approach for all patients with acromegaly.
Most patients with successful surgery for acromegaly feel improvement within a day or two of surgery, primarily related to the rapid loss of excess tissue fluids, especially in their hands and feet. An early assessment of surgical success can be determined by measuring blood GH levels on day-1 after surgery, which should be less than 2 ng/ml within 24 hours given the very short half-life of GH. However IGF-1 levels fall more slowly and hit their nadir 6-8 weeks after surgery.
Long-term neurosurgical and endocrinological follow-up of acromegaly patients who achieve remission is strongly recommended given that late recurrences can occur, typically within 2-5 years after surgery but as late as 10-20 years after surgery. We typically follow our patients with blood levels of GH and IGF-1 and, for some patients, an oral glucose tolerance test every 6 months for at least 2-3 years post-surgery and then annually for at least 10 years.
What if pituitary surgery fails and acromegaly persists?
For patients who do not achieve remission after transsphenoidal surgery, as evidenced by persistently elevated IGF-1 and GH levels, second-line therapy in most patients is therapy with injectable medications such as octreotide, lanreotide, pasireotide and/or pegvisomant. In a subset of patients with acromegaly, addition of an oral medication called cabergoline (Dostinex) may also be utilized. Cabergoline may be particularly helpful for patients who are proven to have GH and prolactin co-secreting tumors. In patients whose MRI shows significant residual tumor or recurrence that is surgically accessible, and who have not had surgery by an experienced pituitary surgery team, repeat surgery may be a reasonable option before resorting to medical therapy. In the small minority of patients who have not reached remission with surgery or medication therapies, stereotactic radiosurgery or stereotactic radiotherapy is the third option. For more detailed information on treatment options, recently released clinical practice guidelines are available: Acromegaly: An Endocrine Society Clinical Practice Guideline (Katznelson et al, J Clin Endocrinol Metab in 2014).
Our experience in acromegaly:
At our Pacific Pituitary Disorders Center, we have a long experience and academic track record in treating patients with pituitary adenomas and acromegaly in particular, including many patients with persistent or recurrent acromegaly. Dr. Kelly’s personal series is over 1800 endonasal operations for all types of pituitary and related skull base and brain tumors, with approximately 80% of those cases being for pituitary adenomas. For the last 8 years, we have used an exclusively endonasal endoscopic approach due to the optimal visualization of the pituitary gland and related skull base anatomy afforded by the hi-definition endoscope. For every case we utilize high-definition cameras and monitors, 3D surgical navigation and Doppler probe for real-time carotid artery localization to maximize effectiveness and safety of the surgery. Our typical pituitary adenoma operation takes about 3-4 hours and most patients are discharged home within 48 hours of surgery.
Be your own advocate to get the diagnosis and treatment right:
Given the complexities of diagnosis and treatment of acromegaly, it is critical that patients seek out a Pituitary Center of Excellence and use available patient and education resources such as these outstanding sites:
Read what patients have to say about their experience in Part 2 of this two-part blog. To learn more, please visit us at www.pacificpituitary.org where you can also see our pituitary-related pituitary publications.
Daniel F. Kelly, MD, and Garni Barkhoudarian, MD, are neurosurgeons with the Pacific Neuroscience Institute in Santa Monica, CA. Pejman Cohan, MD is an endocrinologist associated with the Pacific Pituitary Disorders Center. Together they specialize in the diagnosis, treatment and management of patients with pituitary tumors. Patient advocate Sharmyn McGraw facilitates the longest running pituitary patient support group in the country and is a speaker and author.