The evolving mechanisms of the Growth Hormone – Insulin-like Growth Factor (GH-IGF) axis and their causes of growth disorders
A conversation between Michael Ranke, Tübingen, Germany and Jan-Maarten Wit, Leiden, Netherlands, with contributions by Ze’ev Hochberg, Jan Lebl, Gabrielle Haeusler, Paul Saenger and Margaret Zacharin
Jan Maarten Wit: What were your ideas about the GH-IGF1 axis when you made it to the field of Paediatric Endocrinology?
Michael Ranke: Before I answer, first thank you for inviting me and thank you putting me together with my friend Jan-Maarten. To answer the first question: it’s like always when you start various aspects of your life without really knowing where it is going.
In 1972 I took the chance to continue my residency in paediatrics (which I had started in Düsseldorf under Prof. GA von Harnack) at the University Children´s Hospital in Tübingen, where Prof. Jürgen Bierich had become chairman in 1968. At that time, he was the most prominent paediatric endocrinologist in Germany. The hospital had a laboratory for hormones and biochemical and experimental research headed by Prof. Derek Gupta from London. I was convinced that Tübingen was the best place in Germany to learn the trade of paediatric endocrinology solidly. As the youngest in the group I was of course put on the kind of remnants from the more senior fellows: on the thyroid and on everything that had to do with growth hormone (GH), such as performing the RIA assay, iodination of trace, etc. Thus, I was confronted with the question: How does GH act at the cellular level? Prof. Bierich knew Prof. Bongiovanni from a visit in Baltimore, and Prof. Bongiovanni had the aspiring young professor, John Parks, in his group who had studied at the NIH. John Parks had learned about the B lymphoblastic human cell line (IM-9) from Prof. Jessie Roth. The cell line was used by various famous scientists during these years (e.g. P Gordon, CR Kahn, Pierre de Meyts, Ron Rosenfeld, Ray Hintz) for the study of insulin and GH receptors, including their regulation, internalization, and shedding. This was an exciting new area and a promising tool.
Wit: Can you say something more about what you investigated in your time in Philadelphia with John Parks?
Ranke: I went to Profs. John Parks and Alfred Bongiovanni at the Children´s Hospital of Philadelphia (CHOP) on a grant from the German Research Foundation (DFG) in 1973. The plan was to study the effect of oestrogens on GH receptors in the human lymphoid cell line IM-9 [1], to find the mechanism of the inhibitory effect of oestrogen on growth. Although these studies were without much success, I learned a lot about assays, receptors, numerical analyses of binding, in collaboration with David Rodbard (a famous mathematician at NIH).
I also learned much about GHs (human and from other species) and prolactin. Prolactin was discovered by Henry Friesen from Manitoba, who investigated almost all aspects of prolactin with his many fellows and colleagues (P Kelly, P Hwang, B Posner, a.o.).
At the same time Charles Stanley, who much later made his name on the genetics of hypoglycaemia, did a fellowship at CHOP with Lester Baker in diabetology. He had learned how to isolate viable hepatocytes from rats for metabolic studies. We somehow collided one day and with the different experiences we decided to study the binding of human GH (hGH) and other peptide hormones to these cells. At that time the role and mechanisms of GH interaction with the liver and its role in “somatomedin” (the previous name of insulin-like growth factors) production had not been completely elucidated. It was also assumed before that hGH binds only to lactogenic receptors of the female (or oestrogen-treated male) rat. We were able to show that there are also somatogenic receptors in the rat liver mediating the effects of GH (e.g. IGF production). Interestingly, the lactogenic binding sites to which hGH binds were lost when female rats were hypophysectomized and this could not be restored by oestrogen treatment [2, 3]. These findings and my studies in the field also made me very curious about Somatomedin (SM).
Wit: Back in Germany you became a very successful investigator of Somatomedin and its binding proteins. Please tell us about that.
Ranke: During my absence from Tübingen, Prof. Dieter Schönberg had established the SM bioassay in our lab using the incorporation of radioactive sulfate (S35) into porcine costal cartilage developed by Prof. Leo van den Brande [4], who had trained with JJ Van Wyk in Charlottesville. But then Schönberg had become chairman of Paediatric Endocrinology in Heidelberg, so I took it over. The SM bioassay required utilizing the cartilage from rather young pigs (approx. 3 months old), which incidentally were slaughtered at that age for other scientific reasons at the department of veterinary medicine and agriculture nearby. Thus, every Monday I went to the slaughter house to collect the material and started to measure SM activity in sera of numerous children with various disorders and from rats subjected to endocrine experiments of hormone deficiencies and hormone excess.
While during the years 1975-1980 I amassed a wealth of data with the SM bioassay and had written a PhD thesis about this, SM research had gone much further in various other research institutions. The confusion of the nomenclature (SMC, SMA, MSA, NSILA) disappeared when Rinderknecht and Humbel from the group of Rudi Froesch in Zürich published the structure of IGF-I and IGF-II [5, 6].
By 1980 the group of Froesch (Jürgen Zapf) and Michel Binoux and others had discovered that there were binding proteins for IGF in blood (IGF Binding proteins, IGFBPs). I had established contact with the group in Stockholm (K. Hall, L Fryklund) and in Zürich (J Zapf) and the group in Charlottesville (van Wyk, L Underwood) in order to establish modern assays for the measurement of IGFs [7].
Eventually, the development of assays for IGF-I, IGF-II, IGFBP-3 and IGFBP-2 succeeded and the study of the role of these peptides as diagnostic tools in growth disorders and their functional role in the growth process were studied from 1980 in many groups. In Tübingen this became possible by Werner Blum who was a biochemist and MD and had the “golden laboratory hands”, in collaboration with a number of other researchers in my department [8-12].
The special role of IGFBPs, in particular IGFBP-3, the most abundant IGFBP after birth, is manifested by their high structural complexity. The IGFs, Acid-Labile Subunit (ALS) and IGFBP-3 form a “ternary complex” with a size of about 150 kD, which functions as a reservoir of IGFs in the circulation, inhibits their degradation and functions as their transporter. A genetically caused impairment of ALS was later observed to cause impaired growth [13].
IGFBPs have several functional roles, many of which are associated with the functional regulation of IGFs (IGF-dependent effects), such as (a) the transport of IGFs in plasma, the control and regulation of the efflux from the vascular space and their clearance, (b) the tissue-specific direction of IGFs, and (c) the modulation of the interaction of IGFs with their receptor. For example, the multitude of possible modifications of IGFBP-3 (phosphorylation, glycosylation, proteolysis) can lead to a change in the affinity for IGFs, thus have a functional role for the effect of IGFs. In addition, some IGFBPs may have IGF-independent effects at the cellular level which are of relevance for cell proliferation, cell adhesion, cell migration and apoptosis [14].
It has been fascinating to see that primary defects of IGF production, availability or IGF-I insensitivity have been observed as distinct causes of growth disorders. Examples include GH receptor mutations, genetic alterations in components of the GH post-receptor cascade (e.g. STAT5B , STAT3 and PTPN11 mutations), and IGF1, IGF2, IGFALS and IGF1R mutations. The discovery of new defects in the area is still ongoing [15].
In addition, an excess of IGFBPs, either as a result of renal insufficiency or caused by an impaired cleavage of IGFBPs due to a genetically caused complete absence of PAPP‐A2 proteolytic activity, was shown to diminish circulating free IGFs and consequently result in impaired growth in children [16, 17].
Wit: In your work on the complexity of the IGF/IGFBP system you became also involved in the treatment of GH Insensitivity (for example Laron syndrome). Can you tell us about your opinion about the treatment of recombinant human IGF-I?
Ranke: By 1979 hGH was cloned in E. coli [18] and in 1982 a methionyl-rhGH became available for us in Tübingen from Kabi/Sweden for a phase III study in GH deficiency (GHD). The product had been developed in collaboration between Genentech and Kabi. From 1987 onward authentic recombinant human GH (rhGH) was marketed in Europe.
Recombinant human IGF-I (rhIGF-I) was first used for treatment in primary IGF deficiency (IGFD) by Zvi Laron in 1988, who had first described GH resistance which turned out to be a GH receptor deficiency [19]. Treatment with rhIGF-I was studied subsequently in a cohort with IGFD in Ecuador [20], the USA [21] and by a consortium in Europe which I became involved with [22].
The experience with rhIGF-I treatment, though apparently pathogenetically correct, was not very encouraging. The gain in height was only modest, children were at risk for hypoglycaemia, often developed obesity (an IGF-I effect via insulin receptors) and developed early puberty. One of the remaining problems is that the low IGFBP-3 observed in severe primary IGFD is not affected by rhIGF-I replacement. Observational studies in less severe primary IGFD are ongoing.
Wit: Let me now ask your opinion about some problems that we all have seen surrounding the diagnosis of GH deficiency. First, I would like to hear your opinion about the concept of Growth Hormone Neuro-Secretory dysfunction described in NIH.
Ranke: Soon after GH was measurable by radio-immuno-assay (RIA) in 1963 [23] it was observed that its secretion is pulsatile. Kowarski in the group of Blizzard in Baltimore [24] propagated rightly that the true secretion rate of GH could only be determined by frequent sampling. This is obviously correct, but there are practical hurdles and caveats to this approach. Still, many investigations have shown that there is a low correlation between spontaneous GH secretion over 24 hours and the GH peak after pharmacological stimuli.
In 1984 Barry Bercu and Bessi Spiliotis at the NIH (Bethesda, USA) had described a group of children without known organic damage behaving like children with idiopathic isolated GHD (IIGHD). This condition was termed Growth Hormone Neuro-secretory Dysfunction (GHNSD) [25] and met the following criteria: height less than first percentile; growth velocity 4 cm/yr or less; bone age two or more years behind chronological age; normal findings from provocative GH tests (peak greater than or equal to 10 ng/mL); low somatomedin-C level; and an abnormal 24-hour GH secretory patterns. One might call this “idiopathic GHNSD”. This became an enormously popular diagnosis after rhGH became available.
Not much later the idea of an impaired spontaneous GH secretion in the presence of a “normal” secretion of GH to provocation tests was stimulated by such findings in children after treatment for malignancies [26]. In light of the presumed damage to the hypothalamo-pituitary area one could call it “organic GHNSD”. However, recent investigations have shed doubt on this assumption [27].
I believe that organic GHNSD probably does exist in children after CNS trauma. Idiopathic GHNSD without anatomical CNS anomaly does probably also exist, but is rare (approx. 4% of all GHD) [28].
Wit: In the article you published last year, the frequency was almost 10%.
Ranke: Yes, we stated that it was 10%, but this figure is not a very exact estimate. Again, in my personal opinion, I think that “idiopathic” GHNSD is existing. However, one has to be very thorough to make this diagnosis, because it is statistically unlikely.
Wit: This will be my last question, and then we open the discussion to all participants. There are not only uncertainties about GHNSD, but also about idiopathic isolated GHD (IIGHD). What is in your opinion the best way of diagnosing IIGHD? How frequent is it, and what should be the diagnostic approach?
Ranke: This is one of those 100 Dollar questions in GHD. I do not know whether there is an evidence-based accurate answer to the question. The first reason for this is that it is difficult to establish the diagnosis of GHD. Every paediatric endocrinologist knows the problems of defining an impairment of GHD in children, due to the uncertainties surrounding the tests, cut-offs, etc. Secondly, it is also difficult to diagnose other pituitary hormone deficiencies, for example gonadotropin deficiency before puberty. Thirdly, the term idiopathic means that likely causes of a GH impairment [e.g. brain trauma (mechanic or by irradiation), specific gene defects, anatomical defects of the pituitary region] are absent.
However, despite all of this, I will try to make a reasonable guess based on long-term experience. Based on a review by Frisch [29], the number of isolated GHD in the pre-recombinant era (which was of course also a pre-MRI era) was about 50%. At that time age at GH start was about 11 yrs, mean height SDS was -4, and the GH peak to testing < 7 ng/mL. In our own series < 1987 with similar characteristics the relative frequency of isolated GHD in so-called idiopathic GHD was 39% [30].
I would conclude that with all the additional diagnostic tools available, IIGHD is even less frequent today. In children with very severe GHD (max GH < 3 ng/ml to tests) and in children diagnosed very early (< age 3 years) IIGHD is likely to be less frequent [31].
Wit: Thank you very much; we open the discussion to the participants.
Ze’ev Hochberg: Despite the tremendous progress through the years in understanding the mechanisms through new molecules and their mutations and polymorphism, we still know very little about the why question. Why it is that one child is shorter than another? What we do know is that this is programmed very early in life. If you look for example at the studies of children who immigrated to America from Guatemala, you can see that within a single generation they grow taller by 4-6 centimetres, and all of it within the first three years of life. So something in the environment of the child moving to America makes it grow better than it would have grown in Guatemala. And of course we know that there is the effect of a psycho-emotional stress on the child. I think we probably overemphasize the effects of GH. We concentrated on giving GH to too many children, and lost this important question of why things happen the way they do. You have previously introduced the neuro-secretory dysfunction; this forgotten entity is probably the mechanism explaining how growth responds to the environment. So, its role may be central.
Ranke: These are complicated questions. First let me dwell a moment on the issue of what regulates height. First the observation by James Tanner that normal linear growth was directed towards a target inherited in equal parts from the parents and his subsequent theories about a central “sizostat” has influenced our thinking [32]. However, animal experiments in rats conducted in the 1980 have already suggested that catch-up growth is not associated with an increase in GH secretion [33]. Thus, the neuroendocrine theory of CUG was not fully substantiated empirically. Nevertheless, animal experiments have shown that both systemic (liver-derived) and local IGF-I and GH are required for normal longitudinal bone growth [34, 35].
A new approach of thinking was proposed and experimentally documented by Jeffrey Baron who put the focus on the growth plate as the major determinant of linear growth. It is known that cells of the cartilage lineage undergo a transition from resting (stem) cells to proliferating chondrocytes to hypertrophic chondrocytes until calcification ends the process. The magnitude of the process – from origin to senescence – , that is the number of cell divisions, is obviously under genetic and humoral (endocrine, paracrine, autocrine) control. The normal course of the process requires an intact “milieu interne” – including nutrition, hormones etc. Baron’s amazing suggestion was that in the case of disorders inhibiting growth the process of cell senescence in the growth plate is interrupted. When the defect is corrected the “resting” system “awakes” and the missed process occurs at a faster pace, resulting in CUG [36].
So the question is what is the mechanism how adaptation to the environment takes place, and what do we mean by “environment” actually? The adaptation is to food, quantity and quality, it is to altitude, just to name few things. In the Andes people are short and the Masai are tall, despite the environmental difficulties. What causes the adaptation I don’t know. One other area that has stimulated thoughts and some ideas about this is intra-uterine growth, and its inhibition. I found it, like you do, extremely interesting that these adaptation progresses do not occur through multiple generations, but within a short time. Another example comes from palaeontology. In Sicily there used to be African elephants, who still had the possibility to walk uninhibited over land to Sicily. When the water came into the Mediterranean and separated Sicily from Africa, the elephants were captured, and in this “extra-African” environment, that did not give them enough food. The elephants within generations shrunk to the size of a horse. So there is “something” going on, which is not simply understood by hormone secretion or food adaptation. This “something” must occur on an adaptational level which is possibly epigenetic and is affecting hormones, the growth plate and other levels of metabolism. I can only speculate, but this is one of the things that deserve research.
Jan Lebl: You mentioned the importance of the acid labile subunit (ALS). What’s your opinion on the significance of investigating children for a defect in the gene encoding ALS (IGFALS)?
Ranke: The ALS story is really very interesting. Patients with IGFALS defects vary in stature; some of them are short, some are not. This is the interesting part. In general, measurements of ALS may be valuable in the differential diagnosis of short children with low IGF-I and IGFBP-3 [37]. I know ALS deficiency from the literature, but I have no personal experience with such children. Perhaps somebody around the table knows more about this.
Wit: Yes, it is an important diagnosis and a specific diagnostic clue is that IGF-I SDS is low and IGFBP-3 SDS even lower. What we do as a next step in such children is perform DNA testing and check for an IGFALS defect. We found in 5 big Turkish families that they are often born SGA, so ALS deficiency should be part of the differential diagnosis of SGA as well as of ISS.
Gabrielle Haeusler: Yes, ALS is interesting not only because primary ALS deficiency has a phenotype. We decided to introduce an assay for ALS determination and developed reference data in children. We did so because we wanted to investigate the possible role of ALS determination in the biochemical diagnosis of GHD. ALS like IGFBP-3 and IGF-I is decreased in GHD, it follows the same cascade of GH signalling. What we found is that ALS determination is of no additional benefit as compared to determination of IGF-I alone. Also, routine determination of serum ALS during diagnostic work-up for short stature did not lead to diagnosis of further patients with an ALS mutation. If you suspect ALS deficiency, it’s because of low IGF-I and IGFBP-3. IGFALS is a small gene with two exons, so the genetic analysis is relatively easy and therefore preferable.
Paul Saenger: It is impossible to separate environmental impact on growth from nutritional factors. We heard about small elephants in Sicily, as an example of adaptive downsizing. There are many examples in other parts of the world. On the Channel Islands in California they found small Mammoth skeletons – adaptive downsizing to nutritional restrictions is the guiding principle. Homo floresiensis was very small, maybe because they lived on the tiny island of Flores (Indonesia). Eager colleagues in Pediatric Endocrinology tried to explain it as congenital hypothyroidism or even more esoteric – as the first example of Laron Syndrome. In my opinion, this was just another example of downsizing because of nutritional limitations.
Margaret Zacharin: The question is if in children growing up here in Austria, where there is plenty of food, there is any impact of food. In children in Africa where the children have little to eat one can presume that poor nutrition has an influence on growth, but in rich countries … (?).
Ranke: I think that the impact of what you are mentioning is that some people (even paediatric endocrinologists) are selling food components suggesting that these make children grow. On the other side, this belongs to an area that has not been investigated in a scientifically sound mode. Growth plays on nutrition, but the mechanisms are obviously quite complex.
Zacharin: In IGHD, which seems to resolve in 75% of cases at the end of linear growth, good health and energy remain when demands for GH and growth factors are low, in contrast to a group of irradiated individuals who, when they cease their GH for GHD, at the end of their linear growth, feel dreadful and remain unwell until GH is replaced. Do you have an explanation?
Ranke: These are two things. Are you talking about delay of growth as a part of idiopathic short stature (ISS)? That is something that has been researched and suggested in the 1980’s.
Zacharin: I am really talking about GHD.
Ranke: I want to make this point. In delay of growth and adolescence GH secretion appears low in pre-puberty. However, in the presence of sex hormones eventually all such deviations are gone. In contrast, when a child had a head irradiation, the GH secretory system remains defect. It might well be that these patients are not recognized during the growth phase, but are recognized as GH deficient in adulthood.
Zacharin: The adolescent who has bona fide isolated GH deficiency – not ISS – confirmed by retesting at the end of linear growth does not have associated reduced energy anywhere near the level of disability experienced by those who have radiation induced deficiencies even though other hormones are adequately replaced. Marked resolution occurs with administration of adult levels of GH. It seems unclear as to why this should be so.
Ranke: This is true.
Haeusler: I agree that what we face is this high proportion of patients with IIGHD who reverse their diagnosis in puberty. Are you aware of any study – very complicated for ethical issues- on young children who received low doses of sex steroids, and have been investigated to see if GH secretion normalizes? And growth? The pathological GH test normalizes after giving sex steroids to a child.
Ranke: You are raising this issue when you have a child who is short, not growing well, you did all the tests and you have low GH secretion, and you assume that the child has IIGHD. And then after years, you repeat the test, and then you cannot confirm the diagnosis (according to the established criteria). Then the question is: was your diagnosis wrong in the first place, or was the diagnosis correct but did the “defect” normalise in the end? In my view there is currently a tendency in the scientific community to say that what you have diagnosed earlier in childhood was more likely wrong than correct. Indeed, there was and is perhaps a trend to overdiagnose IIGHD, caused by parents, physicians and producers of rhGH. The question is, whether this can be avoided. Perhaps by “priming” children with sex steroid before GH testing? Some believe it, some do not. Certainly there will and need to be further expert meetings on the whole complex of establishing the diagnosis of GHD in the future.
Wit: Our time is up, thank you all.
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