Role of IGF-1 in the Treatment of Growth Failure

CARLOS R. HAMILTON, JR., MD, FACE: Hello, I'm Dr. Carlos Hamilton. Welcome to the AACE Clinical Conversations. In this program, we will be discussing the role of IGF-1 in the treatment of growth failure.

Joining me to discuss this topic is Dr. Naomi Neufeld, practicing Pediatric Endocrinologist at the Neufeld Medical Group and Clinical Professor of Pediatrics at UCLA School of Medicine in Los Angeles. Also with us is Dr. Paul Saenger, Professor of Pediatrics at the Albert Einstein College of Medicine in Bronx, New York. Thank you both for joining us today.

Dr. Saenger, can you describe for us the endocrine mechanisms of action of IGF-1?

PAUL SAENGER, MD, MACE: IGF-1 is made in response to growth hormone. It is made predominantly in the liver, but also at other sites in the body; in the periphery, probably also at the site of action that is at the growth plates.

So what does IGF-1 do? It is important and a requisite for orderly growth. It stimulates at the cellular level glucose uptake. It stimulates glycogen and protein synthesis and amino acid transport.

All of these processes together will then lead to growth.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Neufeld, can you describe for us what factors influence IGF-1 levels, such as, you know, activation of these receptors or the genes that are involved in the production?

NAOMI NEUFELD, MD, FACE: Growth hormone, in fact, is important. It's the hormone that activates the process whereby the liver is capable of generating IGF-1. And if you look at the slide which we've prepared, you can see

There is activation at the level of the cell surface for that receptor, and within the cell itself, there are several steps that the activated receptor will trigger, all of which need to be intact in order for IGF-1 to be produced.

CARLOS R. HAMILTON, JR., MD, FACE: So the general medical condition of the patient has a lot to do with the effects of growth hormone on IGF-1. If the patient has illness of other sorts that are interfering with growth, that could be one of the mechanisms.

NAOMI NEUFELD, MD, FACE: Well, clearly that's true. So that when you're evaluating a child and looking specifically at IGF-1 levels, you need to make sure that they've had their normal diet. They can't have come off the flu where they haven't eaten for several days and for you to expect a normal IGF-1 level.

So you need to make sure that they're in good health, that they're free of chronic illnesses, such as renal disease.

Liver disease of multiple sorts can result in low circulating IGF-1 levels, as can chronic medical conditions such as cyanotic congenital heart disease, pulmonary disease, including cystic fibrosis.

CARLOS R. HAMILTON, JR., MD, FACE: So -- but you can have low IGF-1 levels despite the fact that the child may have normal or even elevated levels of growth hormone.

NAOMI NEUFELD, MD, FACE: Oh absolutely. When you look at the second figure that was prepared, you can see that growth hormone can be present binding to the receptor, and within the cell itself, there are several steps at which there can be an abnormality, a deficiency, an error in the way that one -- that one gene is working.

That can result in low IGF-1 levels, as can a block for -- against growth hormone binding to the receptor itself. Certainly in the situation of growth hormone antibodies, you can see an inhibition of the growth hormone binding to the receptor so that process will not be stimulated.

And lastly, as was mentioned, adequate nutrition needs to be present as well. If a person is starving, you can see very high growth hormone levels and very low IGF-1 levels.

CARLOS R. HAMILTON, JR., MD, FACE: So there are many steps in this cascade that could interfere with the action of growth hormone on IGF-1 and perhaps even on IGF-1 on the end organ tissue.

NAOMI NEUFELD, MD, FACE: Absolutely.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Saenger, what criteria are used in the diagnosis of primary IGF-1 deficiency?

PAUL SAENGER, MD, MACE: Primary IGF-1 deficiency is a multifaceted entity. Some of the patients have growth hormone resistance. That is they cannot respond to the endogenous -- that their produced growth hormone is actually high, but it fails to generate adequate IGF-1 levels. This is a typical hormone resistance disease best described by Zvi Laron about 50 years ago.

But then we also have other conditions that are much more common than Laron syndrome that may also go along with subtle IGF-1 deficiency. Even some patients have been described who presented with idiopathic short stature -- that is normal growth hormone levels, but IGF-1 levels that were in the low normal or in the range that is defined as abnormal.

CARLOS R. HAMILTON, JR., MD, FACE: We often hear about patients that have complete deficiency of growth hormone from birth, and those are relatively rare examples, are they not? I mean, even children that have pituitary gland disease may have very low levels of growth hormone. Is that correct?

PAUL SAENGER, MD, MACE: That is correct. The general prevalence of growth hormone deficiency is about 1 in 4,000, so it is almost as frequent as congenital hyperthyroidism, for which we are testing with filter paper every newborn in this country.

However, there are some conditions that lead to growth hormone deficiency due to gene mutations. Nothing to do with the formation of the pituitary gland itself or its anatomy, but these are mutations leading to abnormal and totally deficient growth hormone production.

So this child never has seen any growth hormone in its circulation. Growth hormone therapy in these children will lead rapidly to formation of high titer antibodies...

CARLOS R. HAMILTON, JR., MD, FACE: Well that's what I was going to ask you because these children that are naïve, their immune systems are naïve to growth hormone will develop immunity to it, and obviously fail to respond to treatment.

PAUL SAENGER, MD, MACE: Yes. Growth hormone treatment will lead to antibodies. Blocking antibodies, making growth hormone therapy useless. Again, these children are prime candidates for IGF-1 therapy, which is presently the only means to get their growth rates increased or back to normal.

CARLOS R. HAMILTON, JR., MD, FACE: And you would suspect this in patients that had initially responded to growth hormone with increasing their growth rate, but then had failed to continue that response? Can you test for antibodies to growth hormone rather easily in the laboratory?

PAUL SAENGER, MD, MACE: Yes. That has been available for some time. You have to measure antibody titers. There are always low titers that are more frequently seen, but that have no biologic significance. They're probably just immunologic white noise.

However, in these patients that have growth hormone deficiency due to gene mutations, the titers are so high that they make growth hormone totally ineffective.

CARLOS R. HAMILTON, JR., MD, FACE: So when you see a failure to respond to growth hormone in the presence of these high or relatively high growth hormone binding antibodies, you have pretty much established that diagnosis, and then IGF-1 might be the right -- the best treatment. Is that right Dr. Neufeld?

NAOMI NEUFELD, MD, FACE: That's correct.

CARLOS R. HAMILTON, JR., MD, FACE: Has there been much experience with this -- with using IGF-1 in the treatment of these patients?

NAOMI NEUFELD, MD, FACE: IGF-1 has only been available for widespread use since 2006, although there have been some clinical trials preceding that -- the approval of IGF-1 by the FDA.

CARLOS R. HAMILTON, JR., MD, FACE: So this is a fairly new treatment, and there undoubtedly is going to be a lot of research coming out about this in the future that we'll be looking forward to hearing about.

NAOMI NEUFELD, MD, FACE: Well, what it's allowed us to do is allowed us to look at growth as more than a one-horse show, meaning that there is not just growth hormone now out there. And for some children, such as Dr. Saenger mentioned, who are growth hormone deficient but can't respond because of antibody production, this seems to be an -- obviously the choice.

There are other children who have some adverse effects to growth hormone that interfere with the use of growth hormone in their therapy and it -- this provides an interesting opportunity to investigate those children as well.

CARLOS R. HAMILTON, JR., MD, FACE: With growth hormone widespread availability and now IGF-1, there is an opportunity to intervene in this physiological cascade in multiple levels.

PAUL SAENGER, MD, MACE: It may actually also be an aspect of future research to combine the two therapies. It actually has been shown...

CARLOS R. HAMILTON, JR., MD, FACE: Tell us a little bit about that. How would that...

PAUL SAENGER, MD, MACE: Well it actually has been shown so far only in animal data using rodents that the combined therapy of growth hormone and IGF-1 led also to a significant enhancement of their growth.

However, this is something that has never been tested in humans, and I am sure at some point studies will be undertaken to test this hypothesis, whether combined therapy is something that has clinical utility.

CARLOS R. HAMILTON, JR., MD, FACE: You know, one thing we didn't mention in evaluating these patients that have growth failure early on is that not only can you have a gene failure to produce growth hormone, but you can have a lesion of the pituitary gland, such as pituitary adenomas or other types of neoplasms. How common are those, and I assume most of these patients would have an MRI of their pituitary gland...

NAOMI NEUFELD, MD, FACE: That is part of the evaluation. These tumors, these pituitary tumors, craniopharyngiomas and other tumors, are fairly rare, but one of the standard followup procedures when you identify a child with growth hormone deficiency using stimulation testing is to perform an MRI of the brain to make sure that they don't have a brain tumor before any kind of growth therapy is attempted.

CARLOS R. HAMILTON, JR., MD, FACE: We just hadn't mentioned that, and I thought that might be worth bringing out because it...

PAUL SAENGER, MD, MACE: If you want to have a word about the frequency of this condition, which we call organic growth hormone deficiency because it's secondary to some discernible cause -- mostly picked up by MRI -- is in most clinical studies about 15-20% of the total patient collective. So it is a sizable subgroup of children.

CARLOS R. HAMILTON, JR., MD, FACE: Yeah. So those patients would obviously be treated surgically if that's appropriate, and then possibly...

NAOMI NEUFELD, MD, FACE: Surgically, right.

CARLOS R. HAMILTON, JR., MD, FACE: ...treated with growth hormone or...

PAUL SAENGER, MD, MACE: With growth hormone and supplementation of other...

CARLOS R. HAMILTON, JR., MD, FACE: ...or with IGF-1.

PAUL SAENGER, MD, MACE: ...other pituitary hormones that are lacking.

CARLOS R. HAMILTON, JR., MD, FACE: Right. So these things would all have to...

NAOMI NEUFELD, MD, FACE: I think the intriguing thing about having growth hormone and IGF-1 available now is that it allows us to look at short stature growth failure in a somewhat different way, in a much more - it sort of opens the door to look at these children without just being recipients of growth hormone, but we can look at the metabolic actions of growth hormone. We can see if there are other ways of treating them. We can actually use a more tailored response tailored to the individual child, as opposed to giving them a -- pardon the pun -- one-size-fits-all form of therapy.

CARLOS R. HAMILTON, JR., MD, FACE: You had mentioned earlier Dr. Saenger that the administration of growth hormone to children, especially if it started relatively early and can be continued for five, six or more years, can achieve an average growth that you would expect for someone of their genetic makeup. Is this also true of IGF-1 if you administer it over a period if time, and since it's only been available for such a short time, maybe there is not that sort of data?

PAUL SAENGER, MD, MACE: We don't have the data. We do have the data, however, on the patients with growth hormone insensitivity, the Laron type patients.

Now treatment data in those patients have been published exceeding seven to eight years of therapy. But I have to say that their response lags behind the response we typically see with growth hormone in growth hormone deficiency patients. Their growth rate may go from 3 centimeters to 8 centimeters on average in the first year, but then quickly it's followed by attenuation. And their final height is still significantly below what's the average height.

CARLOS R. HAMILTON, JR., MD, FACE: Well idiopathic short stature is obviously a very complex condition that involves a lot of potential problems, so there may be some patients that don't respond as much as you might expect them to or want them to. But that there are a lot of patients that do respond if you can select and administer the proper treatment.

PAUL SAENGER, MD, MACE: That is correct. These patients that are currently under study are patients that have been recruited based on their IGF-1 levels. In other words, their IGF-1 levels were more than minus two standard deviations and the patients were short.

These studies are currently in progress. We do not know at the present time what is their growth response, what is their height, what is their height velocity. So this is something which we all are most keenly awaiting.

CARLOS R. HAMILTON, JR., MD, FACE: I want to thank both of you for being with us today. This has been a very interesting, and I think, informative presentation.

And again, thank all of you for watching, and I’m Dr. Carlos Hamilton. Thank you very much.