Endocrinology

The Metabolic Properties of Growth Hormone

02/10/2022

In this podcast, Rohan Henry, MD, MS, speaks about his research, “When They’re Done Growing, Don’t Forget They May Still Need Growth Hormone,” including the issues impacting the diagnosis of pediatric growth hormone deficiency and the metabolic implications of deficiency.

Additional Resources:

Rohan Henry, MD, MS, is a pediatric endocrinologist and an attending physician at Nationwide Children’s Hospital. He’s also a faculty member at the Ohio State University College of Medicine in Columbus, Ohio.

 

TRANSCRIPTION:

Jessica Bard: Hello, everyone. Welcome to another installment of "Podcast360," your go‑to resource for medical news and clinical updates. I'm your moderator, Jessica Bard, with Consultant360 Specialty Network.

Pediatric practitioners should be cognizant about the metabolic effects of growth hormone. They should also guide patients in adherence to growth hormone therapy. Dr Rohan Henry is here to speak with us today about his review titled, "When They're Done Growing, Don't Forget They May Still Need Growth Hormone."

Dr Henry is a pediatric endocrinologist and an attending physician at Nationwide Children's Hospital. He's also a faculty member at the Ohio State University College of Medicine in Columbus, Ohio. Thank you for joining us today, Dr Henry. Can you please give us an overview of that review?

Dr Rohan Henry: Thanks for having me, Jessica. Most persons are aware of the growth-promoting properties of growth hormone. But there seems to be less awareness of the metabolic consequences, which can happen in untreated growth hormone deficiency.

In our podcast, before I had spoken about not everybody who gets growth hormone truly has growth hormone deficiency. However, there are a couple of persons who are diagnosed with growth hormone deficiency who have a permanent growth hormone deficiency.

Some of those children include those with congenital defects and those with acquired problems with growth hormone, for example, if they have received radiation therapy.

The issue behind this is that because some of these persons with permanent growth hormone deficiency have metabolic problems, that can have implications for them later on in life, even after they're finished growing, hence the title, “When They’re Done Growing, Don’t Forget They Still May Need Growth Hormone.”

Jessica: How did this review come about, and what is the background?

Dr Henry: I'm heavily involved in clinical practice, and one of the patients I came across a couple of years ago was a 17‑year‑old Caucasian female. She had several hormonal insufficiencies, which included genetic deficiency. She had a problem with initiating puberty. She was on hormonal medication for it, so hormonal contraceptive pills.

She also had TSH deficiency, which is secondary hypothyroidism, which is initiated from the pituitary gland. She had a history of receiving radiation for her medulloblastoma. When she came to our clinic, she was really short. She was way below the growth chart. She was about like minus 3.1 centimeters, below the growth chart.

I said to her mom, "Had anybody spoken to you about the fact that she is likely to be growth hormone deficient?"

She said, "You know what? When she was being treated for her medulloblastoma, they had mentioned that, but it was on the back burner because there were more serious issues apart from growth hormone deficiency to think about, such as those things, which would be kind of a life‑or‑death situation."

I took it there and then that she's growth hormone deficiency but didn't do anything about it. Low and behold when she was about 20 years old, she was undergoing routine surveillance by the hematology/oncology clinic, like most of these persons with cancers.

She was diagnosed as having abnormal hemoglobin A1C. Hemoglobin A1C was 9, which anything above 6.5 on 2 different occasions can be classified as having diabetes. I was perplexed as to why she all of a sudden developed diabetes, which she had this profound insulin resistance.

She was about 50 kilos and she was requiring about 155 units of insulin, which is a bottle of insulin. In terms of how we think about insulin, we usually think about it in terms of units per kilogram per day. That was working out to be about 3 units per kilogram per day.

She was coming towards the end of puberty where you'd expect that she shouldn't be that insulin resistant. I went to the literature and realized that there is an association with growth hormone deficiency and insulin resistance, which is not what we would think of as an endocrinologist.

Endocrinologists, we always tell our families, if you keep up with growth hormone, you actually can have glucose abnormality, so you can develop symptoms of diabetes. The converse is true in that growth hormone deficiency can cause profound insulin resistance, like this person was presenting.

The literature also documents about in 1997, there was a young gentleman, who was 17 years old at the time. He had panhypopituitarism. He had a problem with producing thyroid hormone from the pituitary gland, which would be initiating via a TSH. He had a problem with producing ACTH, so he was secondary adrenal insufficiency.

He had a problem with growth hormone production. His fatty liver was only treated effectively once he got growth hormone supplementation. By seeing that case, I drew up to say, you know what, this particular patient who had panhypopituitarism, he had a history of a fatty liver, which is a mild form of insulin resistance.

My patient, who had severe diabetes, had a severe form of insulin resistance because she required so much insulin. My thought was that if his fatty liver was ameliorated by giving them growth hormone, my patient's diabetes could be ameliorated by giving her growth hormone. However, it wasn't totally ameliorated.

She had a significant decrease in her insulin requirement. The issue why it could not have been reversed was that she started having some irreversible changes in her liver. She developed a fatty liver, she had progressed to developing some nodules, on her way to cirrhosis.

She was passing through what we call steatohepatitis, which is just those changes are part of fatty liver, which encompassed inflammatory changes. She couldn't be reversed at that point in time.

Jessica: What are the issues impacting the diagnosis of pediatric growth hormone deficiency and therapy?

Dr Henry: We had touched on what we said in a previous podcast. In a nutshell, I think we could classify the issues broadly as those of assay problems, meaning how the test is done, the issue of how the reporting of the test is done, and the issue of just the test itself.

When we look at the issues of assays, so years prior growth hormone was quantified by a special method called radioimmunoassay, which is an older method by which you look at hormones. More recently, it has been quantified by more-specific methods.

When you say specific methods, you mean that will the assay picks up the values better than it used to before, so you can actually get a lower reading. That's what we call an immunochemiluminometric assay method, which is more specific. You expect that the values of the growth hormone that you're getting are going to be lower with these assays.

Despite as we have discussed before that we're using actually higher values to make the diagnosis of pediatric growth hormone deficiency. The other issue is that not all levels of growth hormone are considered to be equal, per se.

In my field of endocrinology, we treat a lot of patients with diabetes and we rely on hemoglobin A1Cs, which I portable in the sense that you can compare hemoglobin A1C, from one lab to the other lab. We have these point of care machines in most of our clinics.

Years ago, there was a method to harmonize hemoglobin A1C, so you can compare between different organizations' lab work. With the growth hormone assay, some countries do use an international reference corporation which is a standardized we are quantifying growth hormone. Some places use a different reference population.

There hasn't been any standardization, the lack of harmonization may be hard to compare a growth hormone level, per se in Argentina versus that which is done in the US. Apart from those two issues that I just mentioned, there are also issues with the stimulation test itself.

The stimulation test is considered to be the gold standard these days in terms of making a diagnosis of growth hormone deficiency. However, the real gold standard is no longer in use. We used to use an insulin tolerance test, but as you can imagine, giving insulin can cause profound hypoglycemia, it also can cause seizures.

That has fallen out of favor with most practices these days. We're using other agents, which are kind of surrogates for instant tolerance.

Some of the agents are arginine, glucagon, clonidine. Despite the fact that there are different agents, which possibly make stimulate growth hormone production to varying degrees, we use one value as the cutoff for normal, which that value now is about 10 milligrams per ml.

These agents most likely have different stimulations, but we're using one value still. The other issue is that body mass index can affect growth hormone levels. If you look at studies involving persons who have lots of weight tissue, stimulate them afterward, and the growth hormone levels have actually increased.

Despite the fact that we know that body mass index can affect growth hormone levels, we don't adjust for it in clinical practice. The next concept is that of what we call steroid priming. If you look at persons who are late bloomers who have what we call constitutional delay of growth.

If you stimulate them, they can fail the growth hormone stimulation test if you don't give them a certain dose of sex steroids before the stimulation test.

On the normal physiologic circumstances, we have kids who have growth hormone onboard, but at the time of puberty there's an augmentation of this growth hormone response, and that's how you get your growth spurt.

If you were to stimulate that person who is a late bloomer, you could be fooled into thinking that they have growth hormone deficiency because they will fail the stimulation test, but it was a case where that person doesn't have enough sex steroid on board.

The recommendation of the Pediatric Endocrine Society since about 2016 is that sex steroid priming should be done in these patients, who have some constitutional delay. The other issue which affects the growth hormones stimulation is a lack of reproducibility.

If you do a test today, you may get a different value tomorrow if you do the test. There are lots of different variables which can affect the growth hormone stimulation test.

Jessica: What are the metabolic implications of deficiency?

Dr Henry: I want to preface this question by just giving you a background. Recombinant human growth hormone was approved in 1985 by the Food and Drug Administration here in the United States for children.

In about 1987, it was approved for the treatment of adults, who had congenital defects or acquired issues with growth hormone production.

Even prior to that time, it was you're theorized that there was a separate growth hormone deficiency state which was characterized by abnormalities and muscle mass decrease psychosocial well‑being, but there wasn't the wherewithal to do any studies because there was a limited supply of growth hormone.

One of the earliest evidence that growth hormone can have metabolic effects was when you look at the population of adult males with panhypopituitarism, those who were supplemented with other hormones apart from growth hormone, together with growth hormone, they had a better outcome as compared to those who were supplemented without receiving growth hormone.

The fact that if you were supplementing without growth hormone you had decreased life expectancy would make one theorize that there were some metabolic aspects of growth hormone. When you look at the metabolic aspects, there are problems in terms of lipid abnormalities, problem in terms of glucose abnormalities.

One of the issues with lipid abnormalities is that in men with hypopituitarism, they can develop non‑alcoholic steatohepatitis, or fatty liver. The other issue with metabolic aspects of growth hormone is that persons who develop growth hormone in terms of child onset, are different from those who develop growth hormone in adulthood or later on in life.

There is evidence to show that growth hormone may affect cardiac function, so things like your cardiac myocytes. Growth hormone may increase cardiac myocyte activity by modulating the cardiac function. The other issue is that growth hormone can affect bone mineral density positively.

I want to say, even though there are these effects which have been seen in the literature, there is sometimes a controversy as to whether or not these defects are always seen because there's a difference in terms of for the studies have been done. I don't think at this point, we can actually say everybody who is growth hormone deficient should get it.

It's a case where you have to vet each person to see if that person will benefit from getting growth hormone. One thing I didn't mention was that in the adult population, we talk about quality of life.

Growth hormone has been shown to improve the quality of life, in terms of energy level, terms of sexual functioning, growth hormone has been shown to improve some of those parameters and there is a different validated quality of life questionnaire, which you can use to see that the person is improving after they received growth hormone over time.

Jessica: What would you say are the overall take‑home messages from your review?

Dr Henry: The take‑home message is really that we should recognize that there is a role for growth hormone supplementation even after growth is finished. It's important that patients be transitioned appropriately to receiving growth hormone supplementation even after growth is finished.

When I talk about transitioning, transitioning our old body of literature which encompasses change of care, from pediatric to adult population. That's a very crucial time when many persons are lost by the wayside in terms of receiving care, especially with growth hormones.

Growth hormone, for the most part, was given by a shot, which I will come to that later on possibly in the podcast. There was injection fatiguing meaning that persons who were receiving growth hormone every day, they don't want to get growth hormone for a lifetime. You can take equal hormones.

That has caused a lot of problems to come up with growth hormone, but I think the commission should be aware that, you know what, they need to stress the importance of compliance. The take‑home message is that we should appropriately transition and to properly stress compliance with this medication.

Jessica: How can this review impact clinical practice?

Dr Henry: In terms of its impact on clinical practice is just to emphasize that it's important that a subset of patients are not just taking this medication just to grow, but there are also taking it for metabolic functions.

Jessica: Is there anything else you'd like to add, Dr Henry? I really appreciate your time and thank you so much for being on the podcast.

Dr Henry: This is a key question, the issue, it's very timely, in the sense that in the past, two or three months FDA actually improved a long‑acting growth hormone preparation for use in the pediatric population. Normally, traditionally, growth hormone was given by a shot per day.

However, the long‑acting growth hormone, you can give one shot per week, and that is only approved for the pediatric population. If we're transitioning somebody to adult growth hormone, they still will have to get growth hormone a shot per day. That isn't approved for the adult population.

Many persons may be wondering if they could use it, but it isn't yet approved by FDA. There are actually studies going on now to see if it could be approved for the adult population. I think this is a very timely topic.

Jessica: I'll keep an eye on that for sure. Thank you again for your time.

Dr Henry: Thanks to Jessica for having me.