How sustained IGF-1 therapy is rewriting growth stories for children with Growth Hormone Insensitivity Syndrome
Imagine a child's body receiving all the right instructions for growth, yet remaining unable to grow properly. This isn't a story of deficiency, but of miscommunication—a condition where the body's growth signals are sent but cannot be properly received. This biological dilemma is the reality for children with Growth Hormone Insensitivity Syndrome (GHIS), a rare genetic disorder that causes severe short stature.
For decades, this condition posed a seemingly unsolvable medical challenge. That is, until scientists developed a revolutionary bypass treatment using recombinant insulin-like growth factor-I (IGF-1).
This article explores the groundbreaking long-term research that demonstrated how sustained IGF-1 therapy can help rewrite the growth stories of these children, offering new hope where conventional treatments had failed.
In a typical growing child, the growth hormone (GH) pathway functions like a well-orchestrated chain of command:
In GHIS, this chain is broken at step two. Despite normal or even elevated GH levels, due to mutations in the GH receptor gene, the body cannot properly utilize this hormone 2 .
The result of this disruption is severe growth failure with children reaching heights as much as 5-6 standard deviations below average 1 6 .
These children often have characteristic phenotypic features including:
The implications extend far beyond stature. Children with GHIS may experience:
Some children with GHIS are born with congenital abnormalities like strabismus, cataract, or cardiac issues 2 . The condition represents a fundamental disruption in one of the body's most critical developmental pathways.
If the problem is a breakdown in the communication between GH and IGF-1 production, scientists reasoned, why not bypass the defective step entirely? This formed the theoretical foundation for IGF-1 therapy.
By administering recombinant human IGF-1 (rhIGF-1), researchers hypothesized they could directly supply the missing growth mediator 2 .
IGF-1 is a 70 amino-acid single chain peptide with a molecular weight of 7.6 kDa, structurally similar to insulin but with distinct functions 8 .
However, administering IGF-1 presented challenges. In circulation, approximately 98% of IGF-1 is bound to IGF binding proteins (IGFBPs), with IGFBP-3 accounting for about 80% of these complexes 8 .
These binding proteins significantly extend IGF-1's otherwise short half-life but also complicate treatment by reducing immediately bioavailable IGF-1. Therapeutic protocols would need to account for this complex biochemistry.
When IGF-1 binds to the IGF-1 receptor on cell surfaces, it activates multiple signaling pathways including:
Promotes cell survival and metabolism
Stimulates cell growth and proliferation
A pivotal clinical research center study embarked on answering a crucial question: Could IGF-1 therapy sustain growth over many years, not just in short bursts? 1
This ambitious investigation followed eight children with confirmed GHIS for an remarkable 6.5 to 7.5 years of continuous treatment—providing the first comprehensive look at the long-term potential of this therapy.
The study implemented a carefully structured approach:
80-120 μg/kg administered subcutaneously twice daily 1
Regular assessment of height velocity, bone age advancement, and organ growth (via ultrasound)
Comprehensive biochemical profiling and documentation of adverse effects
This systematic, long-term design allowed researchers to distinguish between initial growth spurts and sustained growth patterns—critical information for determining the therapy's true potential.
The findings, published in the Journal of Clinical Endocrinology & Metabolism, revealed a compelling story of persistent growth improvement.
| Treatment Period | Mean Height Velocity (cm/year) |
|---|---|
| Pre-treatment | 4.0 |
| Year 1 | 9.3 |
| Year 2 | 6.2 |
| Year 3 | 5.4 |
| Year 4 | 5.5 |
| Year 5 | 5.2 |
| Year 6 | 4.8 |
Source: 1
The data demonstrates that while the most dramatic acceleration occurred in the first year, meaningful growth continued throughout the treatment period, substantially exceeding pre-treatment rates 1 .
| Treatment Duration | Mean Height SDS |
|---|---|
| Pre-therapy | -5.6 |
| After 2 years | -4.5 |
| After 4 years | -4.4 |
| After 6 years | -4.2 |
Source: 1
The consistent improvement in Height SDS confirms that children not only grew faster but were steadily closing the gap with their peers' growth trajectories 1 .
The study revealed broader physiological effects of IGF-1 therapy:
Spleen and kidney growth was rapid in the first 2-3 years of therapy, eventually transitioning to more age-appropriate growth patterns 1 .
Treatment was accompanied by gains in both body weight and fat 1 .
Bone age advanced normally in prepubertal patients, but accelerated during pubertal changes 1 .
No medical breakthrough comes without challenges, and IGF-1 therapy was no exception. The researchers documented several important safety considerations:
IGF-1-related hypoglycemia occurred early in treatment, particularly in younger patients, but this problem typically abated as treatment continued 1 .
Six of the eight patients showed renal length for height more than 2 standard deviations above the mean after 6-7 years of treatment 1 .
Localized fat tissue buildup at injection sites was observed, particularly in patients with less optimal injection site rotation 6 .
Despite these challenges, the study reported "no major adverse changes in biochemical profile" over the entire treatment period 1 .
The authors candidly acknowledged that while effective, "IGF-I therapy is effective in promoting statural growth in GHIS patients, but the growth response is neither as intense nor as well-sustained as the growth response to GH among children with GH deficiency" 1 .
This important nuance helps set realistic expectations for families and clinicians.
No major biochemical changes
Most issues resolve with time
Proper rotation minimizes issues
Response differs from GH therapy
Advancing our understanding of GHIS and developing effective treatments required specialized tools and reagents. The following table outlines key components used in this field of research:
| Reagent/Solution | Function and Significance |
|---|---|
| Recombinant Human IGF-1 | The therapeutic agent itself; used to bypass defective GH signaling 1 5 |
| IGF-1 Assays | Critical for measuring IGF-1 levels; various methodologies exist including immunoassays and LC-MS |
| IGFBP-3 Measurement | Assesses levels of the primary IGF-1 binding protein; important for understanding IGF-1 bioavailability 4 8 |
| GH Binding Protein Assays | Helps characterize the nature of the GH receptor defect in GHIS 2 |
| Genetic Sequencing Tools | Identifies specific mutations in the GH receptor gene; essential for definitive diagnosis 2 |
The success of IGF-1 therapy in GHIS has prompted investigation into its use for other conditions involving IGF-1 deficiency.
For instance, a 2024 report described its application in three siblings with STAT5B deficiency, another condition causing severe growth failure and IGF-1 deficiency 6 .
The response in these patients, while positive, was less robust than in classic GHIS, highlighting the specificity of treatment mechanisms 6 .
Beyond clinical trials, IGF-1 therapy (commercially known as Mecasermin or Increlex) has become a mainstream treatment for GHIS, transforming lives one injection at a time.
Case reports have highlighted the importance of accurate diagnosis, noting instances where children initially diagnosed with GH deficiency were later correctly identified as having GHIS and successfully switched to IGF-1 therapy 9 .
The differential response to IGF-1 therapy across various growth disorders underscores the importance of precise molecular diagnosis before initiating treatment.
The 6.5-7.5 year clinical research center study of IGF-1 therapy in children with GHIS represents a watershed moment in pediatric endocrinology. It demonstrated conclusively that long-term, persistent treatment could yield sustained growth improvements, changing the trajectory of a condition once considered untreatable.
While the growth response may not match the intensity of GH therapy in GH-deficient children, the achievement remains profound—offering a scientifically-driven solution to a complex biological problem.
The story of IGF-1 therapy continues to evolve, with ongoing research refining protocols, managing side effects, and exploring applications in related conditions. What began as a theoretical bypass for a broken biological pathway has matured into a validated long-term strategy, offering children with GHIS not just increased height, but the possibility of a future unconstrained by their genetic diagnosis.
In the intricate dance of growth signals and cellular responses, IGF-1 therapy has proven to be a partner that can keep the music playing for years on end.