Growth Hormone Deficiency Learning Zone
Transcript: Challenges and unmet needs in children
Professor Mehul Dattani, Dr. Charlotte Höybye, Professor Steven Simoens, Dr. Shankar Kanumakala and Dr. Robert Murray
Interview recorded Jul 2023. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
So first of all, growth hormone deficiency, challenges and unmet needs in children. These are my disclosures. And so, I think the causes of growth hormone deficiency can be defined as being either congenital or acquired. And congenital causes are often genetic and associated with structural defects of the brain or with midline facial defects. Acquired can range from trauma, inflammation, CNS tumours, which are one of the commonest causes. And then inflammation such as histiocytosis, and most importantly, treatment for cancers, basically, such as post-cranial irradiation and post-chemotherapy. The others are all much rarer. And so, the diagnosis of growth hormone deficiency, which I'm sure Rob is going to go into in more detail, consists of growth assessment, and that's the auxology, which is key to starting off the whole process, followed by biochemical assessment, neuroimaging, and genetics. The biochemistry is complex and involves measurements of growth hormone, IGF-1 and IGF-binding protein, and other hormones as well. And generally, in the UK, the NICE guideline suggest that each child should have two tests, which can vary depending on the centre that they're being seen at. However, these provocation tests are highly challenging, and I'm sure that they will form a great deal, a big part of the discussion that we have today. So, what are the challenges in the diagnosis of growth hormone deficiency? Well, we've already talked about the tests, and each centre has their own criteria with different cut-offs.
There are a lot of tests, well over 100 combinations of tests. The assays are very different depending on the centre where the child is being investigated. The debates about the usefulness of IGF-1 in the diagnosis. Obesity has an impact. So, obesity is associated with lower growth hormone concentrations. And use of sex-steroid priming remains a source of major debate, and I'm sure, again, this is something we'll focus on. Use of MRI, which is increasingly being used widely and is very important in the diagnosis. And finally, genetic testing, and we're still at a very early stage in trying to understand this, and we'll touch on that. Challenges in the treatment. Well, the standard doses of growth hormone and growth hormone deficiency are 20 to 35 micrograms per kilogramme per day, given subcutaneously daily. And that has been shown to be efficacious with increments in growth velocity to over 10 centimetres per year, and an increase in the adult height which can range from -0.8 to -1.5 SDS depending on the study you read. There are number of factors that influence growth hormone response such as the age at start of GH, the responsiveness, and the adherence. And again, we'll touch on all of these factors. And those factors affecting final height such as the peak growth hormone, the parental height, and the age and height of the start of growth hormone therapy.
The duration of growth hormone therapy is obviously very important as well. And other challenges, variability in the dose, still a lot of controversy over that, and responsiveness. Monitoring safety and efficacy, are IGF-1 and IGFBP-3 useful, and I'm sure we'll touch on the SAGhE study. The impact of high-dose growth hormone and some papers suggesting adverse effects of these. What happens at puberty, should we use higher doses? What about the impact of long-acting growth hormone? And again, we're going to touch on that today. Retesting for growth hormone deficiency and continuation of growth hormone beyond transition. And now, there's a movement towards early retesting in some patients. And then the wider role of growth hormone, glucose homeostasis, body composition, bone strength, cardiovascular benefit, and neurocognition. And then GH safety, so this is a position statement from ESPE, GRS, and the Paediatric Endocrine Society. And many children and adults have disorders in which growth hormone deficiency may be a part, but these disorders give them an inherent higher mortality risk in any case. So, what is the impact of growth hormone in these patients? What's the incidence of developing glucose intolerance or overt type 2 diabetes during growth hormone treatment? And generally, it's very low in paediatric patients with GHD. In a number of big conditions treated with growth hormone, however, lifetime risk of glucose intolerance and type 2 diabetes can be higher than in the background population, and this includes Turner syndrome.
So, we'll move on to the discussion now. And I'll invite other members of the panel to start off the discussions, really. Does anyone want to raise points from the short presentation and lead on it at this point? So, Mehul, one of the biggest factors in the adult sector has been the increase in obesity. And clearly, there now is a epidemic of childhood obesity, which affects all the tests that we are aware of in the provocative tests. How much has that become a factor in the childhood growth hormone deficiency diagnosis? So, I would say that it is quite a major issue, and becoming more so, particularly at the time of adolescence, really. And it is very difficult when you have an obese child who's not growing particularly well, maybe, in front of you, and you're considering all the factors there. So, I tend to go... ...by the IGF-1, if the IGF-1 is low, then I will go ahead and investigate. But the problem is, you know that when you're going to investigate that you might find very low concentrations of growth hormone on testing. And I've had some of these children whom I felt have not really been growth hormone deficiency with complete... You know, lack of GH secretion on a provocation test. So it can be very, very challenging from that point of view. I don't know whether any of the others have had that similar experiences. Charlotte, Shankar? I mean, one of the things that I find a little bit difficult is, we know that IGF-1 levels are smaller or lower in short children, which we are all aware. But is IGF-1 levels, what is that, different in children who are obese?
So, I think that's a difficult question. Generally, if child is obese, it should not impact on the IGF-1 concentration. Now, you know, against that if you have a child with growth delay and their bone age is delayed, then that is a different issue. They may have lower IGF-1. And additionally, the age. Obviously, when we're talking about obesity, it will probably be older children. But in younger children, we've shown that the IGF-1 concentrations, for instance, for the first three years of life are really quite challenging and are often very low, and then they gradually increase and normalise by about four years of age. This is even in normal children. So, it's very difficult to make any decisions in the first three years of life based just on the IGF-1. And you know, you've got to have other sort of pieces of evidence that suggest a diagnosis of growth hormone deficiency, which can then lead you to perform a GH provocation test. But in obese children, in older obese, I generally find the IGF-1 concentrations are normal. And so, that is quite a useful point to take into account. And also, obviously, the growth rate. Remember that obese children will generally be growing at a slightly faster rate, and also, they may have an advanced bone age, which is quite common in obesity. Anybody else got any comments on that? Sorry, Shankar, were you going to say?
Yeah, I mean in all growth hormone registries and treatments, and all those things, there is always a higher preponderance for male children to be detected with short stature untreated as opposed to female children. Does the society accept short stature much more readily in female children, or are we actually missing something that we are actually not picking up short stature that are in female children in particular? So, does anybody want to comment on that before I do? I mean part of it is going to be societal, isn't it, where men are much more worried about their height than females, and I think that's going to be a factor in it. But otherwise, I think I'll hand back to Mehul. Yeah, I mean I think that's a very good point, and I was discussing it just the other day with one of our nurses, and we were just commenting on that, looking at some of our data, and I can't remember which condition it was. And there were only two girls, and they had about 20 boys being treated with growth hormone. Yeah. And so we said, "Well, I wonder if this is actually that boys are more readily presenting, 'cause the parents are more concerned rather than girls."
And I think there is definitely that, even in this day and age in society, that, you know, it's okay being a petite girl but not being a petite male. However, there are certain conditions where there's a preponderance in males, basically, and particularly, congenital hypopituitarism. Yes. Okay. So, there's a two to one incidence of male to females. And increasingly, when we're looking at the genetics, we are finding that there are excellent genes around, and I think there are more to discover as we go along. So, I think there's no doubt that in some conditions there's a preponderance. But yeah, I think societal, sort of, attitudes are still inherent in clinical practise. Thank you, Mehul. Thank you, Rob. Any other points that people want to raise? So years ago, 20 years ago, probably when I was doing a lot more of the treating the cancer survivors, we used to be sex-steroid priming pretty much all of our children who were peripubertal.
That seems to died off quite a bit now, and I wonder what your thoughts are around that. So, shall I start off? I'm a real advocate of sex-steroid priming. And essentially, you know, I use sort of an age of around 10, chronological age, and if they're completely prepubertal, I will always add in priming, and that's the policy in our centre. You're right, Rob. I mean I think there's a lot of controversy over that, quite a lot of European centres, for instance, don't use priming. My feeling is that, you know, priming does make a difference, and there have been studies by Marin, etc several years ago, which showed quite a marked effect, you know, in unprimed and primed individuals in terms of growth hormone secretion. And they performed a very nice randomised study, and when they primed the patients, very fewer, really, patients actually tested growth hormone deficient as compared to unprimed patients. So I think, you know, I would certainly prime.
There's no doubt in my mind. And you know, additionally, we'll talk about maybe GH retesting. But there's now a trend towards early GH testing in early sort of puberty, and these patients are often shown to be normal when they're retested. So, I think the effect of puberty is extremely important. Now these are patients with structurally normal pituitary glands. So, we're talking about almost what used to be called idiopathic growth hormone deficiency. Some of the other groups like multiple pituitary hormone deficiency, and maybe the late-effects patients are going to be more sort of, you know, definitive in terms of their growth hormone deficiency. Any other points? Anyone else in priming? No? Anyone against it completely? No, it doesn't look like that. Okay. Any other points that anyone wants to raise? And I think we'll talk about safety a little bit later, but you know, Rob, I'd really like your views, obviously, on the use of growth hormone and some of the cohorts of patients you've looked after in the past with late effects and things. But maybe we can leave that for a little bit later.
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