Is there an endocrinologist who wouldn’t appreciate the challenge of trying to stop the tallest man in the world from growing?

When the Discovery Channel called to ask Mary Lee Vance, MD, to see Sultan Kosen, Guinness world record holder for his 8-feet, 3-inch stature, his diagnosis of gigantism and acromegaly was clear. But despite the best efforts of doctors in his native Turkey, including two operations to remove a pituitary tumor and ongoing medications, he was still growing in his 20s. The tumor was simply too big and invasive to eradicate, causing the gland to pump out too much growth hormone.

Vance, a professor of internal medicine and neurosurgery at the University of Virginia and a principal at one of the world’s leading pituitary centers, first adjusted Kosen’s medications, then arranged to have him return in a few months so a colleague could perform stereotactic radiation surgery using a Gamma Knife. Th at procedure knocked back the tumor enough that an aggressive combination of medications has Kosen’s disease in check. Two years postoperation, he isn’t growing and his growth hormone and insulin-like growth factor 1 (IGF-1) levels are under control.

A Stealthy Danger

When an 8-foot patient walks into your office, the obvious response is to look to the pituitary for acromegaly, but Kosen’s gigantism, in which the tumor takes hold in childhood, is the rarest form of a rare disease. Most acromegaly sufferers go years before receiving the correct diagnosis. Vance cited a more typical case of a woman who had been experiencing an odd assortment of symptoms for years. Her wedding rings became tight, her shoe size went up two sizes and expanded from medium to extra-wide, her nose enlarged, and she developed sleep apnea and carpal tunnel syndrome. When symptoms like these occur gradually, they’re often blamed on aging.

Th en one day the woman fainted at work and the rescue squad took her to the hospital. An MRI showed an obvious pituitary tumor. In 99 percent of acromegaly cases, the culprit is a benign pituitary tumor, a somatotroph adenoma, causing hypersecretion of growth hormone and often other hormones.

The patient was referred to an experienced endocrinologist, who recognized the disorder with a glance at the patient’s face, hands, and feet. “That’s a very common story. She had had symptoms for 10 years, but no one had ever entertained the diagnosis of acromegaly,” Vance told Endocrine News.

A survey by Vance revealed that most acromegaly patients experience symptoms for 8 to 10 years before being diagnosed. Diagnosis is important because growth hormone affects nearly every tissue in the body, and the disease is associated with at least a doubled mortality risk.

“The morbidity is pretty severe, which is one of the reasons we try to be very aggressive in treating these patients,” Vance said. Normalization of GH and IGF-1 levels can negate the increased mortality and counter many symptoms.

Rare and Present Danger

One factor making diagnosis difficult is the disease’s rarity—four cases per million per year and prevalence of 40 to 125 per million, although some recent studies have suggested that the prevalence could actually be three to five times higher. “It’s very likely that this disease is highly underdiagnosed,” said Laurence Katznelson, MD, medical director of the pituitary center at Stanford University Medical Center. Katznelson chaired a panel for the American Association of Clinical Endocrinologists (AACE) that published treatment guidelines for acromegaly last year.

Another reason that it goes undiagnosed is its creeping, insidious nature. The disease generally begins in adulthood, which means that the long bones have stopped growing, so the patient doesn’t increase in height. However, the hands, feet, facial bones, nose, and tongue all enlarge. Because the changes occur over a period of years, the patient may not find them remarkable.

Clinicians can miss the significance of other symptoms, such as sleep apnea. The rise in obesity is driving an increase in sleep apnea, so physicians may be complacent about looking for an underlying cause, even though these patients are unlikely to be obese. Acromegaly patients can develop sleep apnea because enlargement of the tongue and neck tissues can make it hard to breathe at night. Many common symptoms do not necessarily point to the pituitary (see sidebar).

Both Vance and Katznelson described patients who were treated for heart problems for years, but their cardiomyopathy turned out to be the result of excess growth hormone leading to muscle thickening. “I’ve had two patients on the heart transplant list because their heart was failing. When we treated their acromegaly, it reversed, and they are fine now,” Vance says

Diagnosis and Outcomes

The hardest part of the diagnosis may be thinking of it at all. Once a physician looks for acromegaly, the biochemical diagnosis is straightforward. Screening tests include serum IGF-1 and growth hormone. The IGF-1 level needs to be checked against age- and sexmatched controls. The oral glucose tolerance test remains the gold standard for growth hormone, with a patient’s inability to suppress serum growth hormone to less than 1ng/mL considered diagnostic for acromegaly. Another key hormone to be aware of is prolactin, because it is hypersecreted in about 20 percent of cases.

The next step is dedicated pituitary MRIs, with and without contrast medium, to look for a tumor.

Treatment is complex, involving a multidisciplinary team, but the most common progression remains the triad of surgery, drugs, and radiotherapy.

The best outcome, of course, is physical removal of the tumor, so transsphenoidal surgery is indicated for microadenomas confined to the sella turcica, noninvasive macroadenomas (tumors greater than one centimeter), and tumors that are causing compression symptoms (such as pressing on the optic nerves). The guideline notes that experienced surgeons achieve appreciably better cure rates as well as lower morbidity and mortality.

The smaller the tumor, the greater the likelihood of a surgical cure. But about two thirds of the patients have macroadenomas, perhaps due to the long lag time before diagnosis. And only about 45 percent of these patients experience a surgical cure.

This relatively low success rate, combined with the number of patients who must forgo surgery because they are poor risks or have invasive, inoperable tumors, means that a large proportion of patients require drug therapy to control or counter their hormone overproduction.

Drug and Radiation Therapies

Th ere are three main drug approaches. Dopamine agonists and somatostatin analogs both directly inhibit growth hormone secretion. A growth hormone receptor antagonist interferes with its action by blocking its receptors, thereby leading to reduced IGF-1 secretion.

The AACE guideline considers dopamine agonists to be the first-line medical therapy in patients with modest disease because they are orally administered and less expensive than the other options. There are two, cabergoline and bromocriptine, with cabergoline considered more effective and better tolerated.

Two somatostatin analogs, octreotide and lanreotide, are available in long-acting formulations, both administered by injection, and have the added benefit of sometimes shrinking the tumor. For this reason, they are sometimes given before surgery, either to increase the cure rate or to ease the surgical experience. The AACE guideline concludes there is insufficient evidence to support their use to increase cure rate. The data supporting the theory that they make surgery easier are also limited, but the guideline suggests considering this use on a case-by-case basis, for example, when a patient with a swollen pharynx and surrounding tissues may have difficulty with intubation.

The growth hormone receptor antagonist, pegvisomant, is effective in normalizing IGF-1 values and at improving glucose homeostasis in patients with diabetes mellitus. It is administered by injection.

The drugs are often used in combination when a single agent doesn’t achieve growth hormone and IGF-1 targets.

As Sultan Kosen’s experience shows, radiation therapy is an alternative when patients don’t adequately respond to surgical and medical treatment. In recent years, stereotactic radiation, the most common of which is the Gamma Knife, has been making inroads to replace conventional fractionated radiation. Stereotactic radiation offers the advantage of a focused dose delivered to a limited area in a single operation. Fractionated radiation is delivered through each temple and the frontal area, exposing more areas of the brain to radiation, and is given repeatedly over a six-week period.

“We have treated a lot of patients [with the Gamma Knife] and we see about 52 percent remission rate at about two years after treatment,” Vance says. “Fractionated radiation usually took 10 to 20 years to be effective. We’ve treated over 500 patients with pituitary tumors with the Gamma Knife and we find it to be very safe and effective.”

Katznelson said the guideline committee found no real data to indicate that one form of radiotherapy is better than the other. Although there are some suggestions that stereotactic radiation is faster-acting, the side effect profiles are not significantly different. There’s no evidence of a difference in cure results, particularly over the longterm. Nonetheless, the guideline says: “Because of technical advances and convenience, stereotactic radiosurgery may be considered the preferred mode.”

Either form can lead to a loss of pituitary function, but Vance notes “that’s not so bad because you are preventing tumor growth and curing acromegaly. We can always replace the missing hormones.”

While strides continue to be made in treatment, the biggest challenge remains identifying the patients who need it. Katznelson said that many patients are identified when they change to a new dentist who notices their jaw is growing, change physicians, or see a long-lost relative who wonders why their face looks so different. That’s why the guideline emphasizes the “need to educate primary care physicians and other medical groups about the constellation of signs and symptoms to facilitate earlier detection.”

— Seaborg is a freelance writer in Charlottesville, Virginia, and a regular contributor to Endocrine News.

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