Use of IGF-I to reassess growth disorders

Keeping up to date on the latest research, diagnostic processes and treatments is a career-spanning imperative for all clinical physicians. Good medicine means periodic reassessment of whether our current methods provide the best care possible. This involves stepping back from current techniques and practices and re-evaluating past assumptions.

One area in which there is a particular need to reassess current paradigms is the field of growth disorders. Growth hormone deficiency has been identified for years, and treatment with recombinant GH has been readily available since 1985. More recent research has led to recombinant insulin-like growth factor I being approved for use in children with severe primary IGF deficiency. The development of recombinant IGF-I has provided clinicians and researchers an opportunity to re-evaluate and clarify growth disorders.

Dana S. Hardin

Hormone deficiency models

IGF-I has always been a part of the growth puzzle. Most of the biological effects of GH are mediated by IGF-I, and measurement of circulating IGF-I levels is standard practice in the evaluation of pediatric short stature. Poor nutrition can lead to low levels of IGF-I, and GH deficiency is another possible reason for low circulating values. However, pediatric endocrinologists have noted low IGF-I levels in patients who have “passed” GH secretagogue testing, yet are not nutritionally depleted. These patients cannot be called GH–deficient.

If we follow the model for other hormone deficiencies — for example, thyroid hormone and adrenal hormone deficiency — then it is logical that the reference point for any hormone deficiency should be the biologically active hormone. The active hormone in growth disorders is IGF-I.

Patients with low GH levels are labeled as GH–deficient, but the reason they do not grow is because their circulating IGF-I levels are low secondary to GH deficiency. Growth in these patients improves with recombinant GH in direct correlation to the increase in their circulating IGF-I levels. Thus, patients who have clinically low IGF-I levels and pass GH secretagogue testing in the absence of nutritional issues are in fact IGF-I–deficient, not GH–deficient. Logic would determine that these patients should respond well to recombinant IGF-I.

Debate over IGF-I

There are good data using recombinant IGF-I in treatment; however, recombinant IGF therapy remains more controversial than recombinant GH. Issues expressed by pediatric endocrinologists fall into four categories:

• The belief that IGF deficiency is just another name for idiopathic short stature (ISS itself is a controversial diagnosis).
• The belief that if you give enough GH to patients they will all eventually grow.
• The reluctance to prescribe a relatively new medication with possibly more or unknown adverse effects.
• The reluctance to take on more battles with insurers who expound the belief that growth disorders are a purely cosmetic issue and thus no additional treatment is needed.

ISS vs. IGF deficiency

Several years ago, I sent a survey regarding GH treatment practices to all physician members of the Lawson Wilkins Pediatric Endocrine Society. The results of that survey indicated a great deal of controversy over the treatment of ISS. It seems that some endocrinologists are less receptive to using recombinant IGF-I due to an association made between IGF deficiency and ISS. Since some endocrinologists do not perceive ISS as a need-to-treat, this perceived association can lead to reluctance to use recombinant IGF-I.

Severe primary IGF deficiency is a problem in which the mechanism of the disease is not fully understood. But lacking a full understanding for disease mechanisms is a common treatment challenge that has always existed in medicine — and always will.

Despite no single definitive test for diagnosing IGF deficiency currently, patients with abnormally low growth velocity and clinically low IGF-I levels certainly appear to have a problem in the GH/IGF axis and will respond to treatment with recombinant IGF-I. As physicians, we must make decisions based on available data and choose treatment options that offer the best possible benefits to the patient in each situation. Thus, we cannot ignore the potential for treatment with recombinant IGF-I.

GH for all patients

A second hesitation stems from habitual practices and the fact that GH was the only treatment option available for more than four decades. It is difficult to try a new therapy when there is a belief that the old drug (recombinant GH) works “just fine.” Although some research suggested certain patients may need high doses of recombinant GH to reach age- and Tanner stage–appropriate circulating IGF-I levels, increasing the dose of recombinant GH may be more costly than using recombinant IGF-I. We need to carefully explore the diagnosis of severe primary IGF deficiency and use recombinant IGF-I for these patients.

Accurate diagnosis and precise, targeted treatments are paramount to reaching optimal patient outcomes. When patients are not responding to GH therapy, the value of increasing the dose repeatedly should be questioned instead of re-evaluating the diagnosis and considering implementation of other treatments.

In the case of treating patients with severe primary IGF deficiency, why increase the doses of recombinant GH up to 0.7 mg/kg per week when it is possible to reach equal or greater results by treating with recombinant IGF-I at a lower dose? Having maximum results with the lowest possible dose of the most targeted medication is always a best practice.

Potential adverse effects

A third cause for reticence is potential unknown adverse events due to the newness of the drug. There is a registry for recombinant IGF-I, which physicians use to meticulously record any events. Ongoing safety monitoring processes offer clinicians reassurance and information on patient responses and adverse event rates.

For example, when recombinant IGF-I was approved by the FDA, the potential risks were taken from the findings from children with Laron syndrome. Tonsilar hypertrophy and hypoglycemia were listed in the package insert and understandably have led to caution by potential prescribers. Information released by the patient registry points to only 49 of 685 patients in the registry with episodes of hypoglycemia and nine with tonsilar hypertrophy. It should be noted that hypoglycemia, as reported in the registry, was based on symptoms, not on actual documented blood glucose levels, and these problems may not be as severe nor occur as often in patients without Laron syndrome.

Effect of short stature

Severe short stature is not only a cosmetic issue, and evidence supporting this continues to mount with research into the psychological effect, along with higher rates of diabetes and cardiovascular disease associated with severe adult short stature. This issue offers us an excellent opportunity to reevaluate our endpoints.

It has been long accepted that the purpose of treatment in these patients is to increase the projected final adult height to reach height in the normal range. My experience in studying the metabolic effects of recombinant GH and recombinant IGF-I, as well as study findings from others, suggest that we should consider other endpoints as well. The GH/IGF axis is involved in many aspects of development — not just height. We know that the GH/IGF axis influences bone development and muscle strength. Why not factor these endpoints into our assessment as well?

In summary, with any new treatment or diagnosis, it will take time for it to become part of standard medical practice, and good research ultimately paves the way for that acceptance. The relatively recent approval of recombinant IGF-I for treatment of growth disorders provides a new and exciting opportunity for clinicians and researchers to re-evaluate established treatment paradigms. Whether it is a re-evaluation of endpoints or further research into definitive diagnostic testing, new data on IGF deficiency continue to add empirical weight to clinical intuition. It also gives us another wonderful opportunity to treat patients as individuals — by choosing the best overall medication for their growth disorder. As always, more research is needed.

Dana S. Hardin, MD, is a Pediatric Endocrinologist and Professor of Pediatrics at The Ohio State University College of Medicine in Columbus.

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