Expert Conversations: The Physiology of Growth Hormone Deficiency

In this podcast, authors Julie Silverstein, MD, and Alexandra Martirossian, MD, discuss the physiology of growth hormone deficiency and differences between childhood- and adult-onset growth hormone deficiency. This is part 2 of their podcast series on their recent Consultant review article, "Diagnosis and Management of Growth Hormone Deficiency in Adults."

Additional resources:

Julie M. Silverstein, MD, is an associate professor of medicine and neurological surgery and medical director of the Pituitary Center at Washington University in St. Louis.

Alexandra Martirossian, MD, is a second-year fellow in the Endocrinology Department at Washington University in St. Louis.



Amanda Balbi: Hello, everyone, and welcome to another installment of Podcasts360—your go-to resource for medical news and clinical updates. I’m your moderator, Amanda Balbi with Consultant360. 

In part 2 of our podcast on the article, “Diagnosis and Management of Growth Hormone Deficiency in Adults,” I speak with the authors about the physiology of GHD and differences between childhood- and adult-onset GHD. 

Dr Julie Silverstein is an associate professor of medicine and neurological surgery and medical director of the Pituitary Center at Washington University in St. Louis. Dr Alexandra Martirossian is a second-year fellow in the Endocrinology Department at Washington University in St. Louis.

Let’s listen in as they answer my questions.

What are the mechanisms of action of adult-onset GHD, and how do the mechanisms differ from childhood-onset GHD?

Alexandra Martirossian: Sure, so a fundamental difference between adult-onset and childhood-onset is that usually childhood onset often has a genetic cause, and it is more often an acquired cause. So, at least in the genetics realm, it could be maybe a defect in the gene for growth hormone or the growth hormone receptor verse.

And then acquired can happen in adults and children equally. I would say the most common cause is disorders, like pituitary tumors, and then treatment for those tumors whether that's surgery or radiation. There's a big variety of tumors that can appear in the pituitary. Adenomas are most common, but you can get things like brachial plexus, meningiomas, cranial granulomas. There's a pretty big variety there.

You can get even metastases to the pituitary, and then traumatic brain injury can cause it. And then there can be infiltrated diseases like sarcoidosis or amyloidosis. You can get autoimmune inflammation of the pituitary gland. And you can get infections of the central nervous system, so like tuberculosis or syphilis. And then there could be infarction or hemorrhage in the pituitary gland.

One thing we always have to keep in mind is something called pituitary apoplexy, which is essentially when there's either a hemorrhage or cut off of blood supply to the pituitary gland. This is typically seen in cases where there’s enlargement in the pituitary gland, like a pituitary macroadenoma. Usually, patients will present with severe headaches, cranial nerve palsies.

It can be a surgical emergency, especially if it leads to drops in cortisol or thyroid levels, which are essential for life. Sometimes these patients need to be seen by a neurosurgeon very quickly. When that scenario happens in pregnancy, it's called Sheehan syndrome.

Sometimes, going back to the pediatric realm, there can be the failure of the central nervous structures to develop properly, and that can lead to things like septo-optic dysplasia, for example.

Julie Silverstein: I think the only thing I'd add is that people are becoming more increasingly aware that TBI (traumatic brain injury) and subarachnoid hemorrhage are clinical conditions that can cause growth hormone deficiency.

Amanda Balbi: Making the diagnosis of GHD is generally easier in children because, like you said, the outcome of short stature is readily apparent, and because the symptoms are generally nonspecific for adult-onset GHD. Therefore, a higher index of suspicion is required, as we talked about before. So, what risk factors should raise suspicion for adult-onset GHD?

Alexandra Martirossian: The big thing is just a clinical history. Like, if they have that history of a brain tumor, pituitary tumor, or treatments like surgery or radiation of the pituitary gland or nearby structures, that's a big one. Again traumatic brain injury or if they had a congenital defect leading to growth hormone deficiency in childhood. Those are all things to raise suspicion.

Julie Silverstein: The other thing is that if you have a patient with a pituitary disease or history of surgery, and they have other hormone deficiencies like central secondary hypothyroidism, central or secondary hypogonadism, or secondary or central adrenal insufficiency—especially if they have all 3 of those—then the likelihood that they have growth hormone deficiency is very, very high. That's The other thing to keep in mind.

Amanda Balbi: Okay, so let's talk a little bit more about diagnostic testing for GHD in adults. What tests are currently available to aid in the diagnosis?

Alexandra Martirossian: Well, I guess I'll give a little bit of background about how we go about testing growth hormone in the first place. In general, just checking a random growth hormone level by itself is not helpful, because there's a lot of variables that can affect them; it can include whether you just ate something that can suppress them, the time of day, or if there’s stress and even age. All of those things can affect growth hormone levels.

They also have a very short half-life in blood. I mean, it's just about like 20-30 minutes. Typically, if we’re screening for GHD, sometimes we'll start with the IGF-1 level, because that's a downstream marker of growth hormone production, so see if that's abnormally low. And the history will decide whether you do stimulation testing.

Like Dr Silverstein had mentioned, if you have a patient who has already has 3 or more pituitary hormone deficiencies, like secondary hyperthyroidism, secondary adrenal insufficiency, and then maybe like secondary hypogonadism, your pre-test probability of having growth hormone deficiency is very high.

So, if you have 3 formal deficiencies and a low IGF-1 level less than 2 standard deviations—or it's often reported as a Z score—then your diagnosis is made. You can just empirically treat. If they have 2 or fewer hormone deficiencies and history of pituitary disease and a low IGF-1 level, then you could proceed with stimulation testing.

As far as the stimulation tests go, there are 3 that we use commonly in the United States. There's an insulin tolerance test, the glucagon stimulation test, and a macimorelin test. The first one was the insulin tolerance test. It was one of the earlier ones, and it for a long time and had been considered a gold standard.

The way it's done is the patient fasts for 8 hours and then they're given a dose of insulin. The goal is to get them really hypoglycemic, like their blood sugar less than 40. Then, growth hormone levels are drawn at 20, 30, 40, and 60 minutes. If their growth hormone levels are less than 5 μg/L, then that's a diagnosis. The big drawback with this one is that it can be very unpleasant. I mean, having a critically low blood sugar is not a fun experience for patients, and it can be dangerous. This test is contraindicated in people with a history seizure disorder, history of cardiovascular disease, age older than 65, or pregnancy.

Another one that's a little bit better tolerated is the glucagon stimulation test. This one is similar; you start by fasting and then they're given a shot of glucagon. Then their growth hormone levels are measured over every 30 minutes for 4 hours.

The cutoff in this test is less than 3 μg/dL if the BMI—in lean people—is less than 25 kg/m2. Because obesity can blunt the production of growth hormone, that cutoff is lowered to 1 μg/dL if the BMI is over 25 kg/m2.

Common symptoms are like gastrointestinal things like nausea, vomiting, or sometimes you can have drops in your blood sugar hours after the test. Probably the biggest frustration is that it’s long; it's 4 hours, so it's going to be a big time commitment.

One of the newer tests on the market now, the macimorelin test. It's relatively new. I think it's been on the market for about 3 or 4 years now. This one is oral; they take an oral solution. The patient comes in fasting, they take this oral solution of the macimorelin, and then growth hormone levels are measured every 15 minutes for an hour and a half. The cutoff for this test is a growth hormone level of less than 2.8 μg/dL. Although, some recent studies have proposed raising that cutoff to 5.1. But, at least for now, the FDA cutoff is 2.8.

As for side effects, really the most common symptom is just impaired taste. Otherwise, there’s just cautions for TTC prolongation. I’d say the biggest barrier, though, against its wider spread use is just cost. Because it’s new, so it's really expensive. That's the big thing there, but hopefully in time that will be a more readily used test.

Julie Silverstein: I just want to add that I think we rarely do the insulin tolerance test anymore, because we have the glucagon test because of the risks. Glucagon is widely available, and I think that's what's most commonly used in the United States.

The macimorelin is great because it's an oral test and doesn’t take as long, but cost is the main issue. I think it's difficult to get these simulation tests done outside of centers—you know, like pituitary centers or academic institutions.

You can measure IGF-1 levels, of course, but it's important to realize that patients with growth hormone deficiency can have normal IGF-1 levels. So, that doesn't always rule it out. If you have a higher index of suspicion and you have someone who has, for example, other hormone deficiencies, it's reasonable to go ahead with a stimulation test, whether it's the glucagon or the macimorelin.

The other thing that's important to remember when doing the diagnostic tests is that overweight individuals can have a blunted growth hormone response. So, that's why you'll see now that there is a different cutoff recommended for the glucagon stimulation test based on weight. The cutoff for the glucagon stimulation test in someone who's BMI is less than 25 kg/m2 is less than 3, but if the BMI is higher than that, it's really less than 1.

The macimorelin test has not been really studied yet in obese individuals, so we don't have a difference of the cutoffs in that population.

Amanda Balbi: Thank you again so much for answering my questions.

Julie Silverstein: Thank you.

Alexandra Martirossian: Yeah, thank you for having us.