Treatment of short children with GH plus IGF-I: Are two hormones better than one?

Treatment with growth hormone is an established option for children with short stature due to a variety of causes. Approved indications include documented GH deficiency (GHD), Turner’s syndrome, Noonan’s syndrome, renal failure, intrauterine growth retardation, idiopathic short stature and, in selected cases, Prader-Willi syndrome. Improved growth velocity is a requirement for use in these entities; documented growth improvement varies from satisfactory to significant and sometimes spectacular. Guidelines for dosage use depend in part on the indication and in part on the growth response achieved.

More recently, it was suggested that GH treatment dosage be titrated to target insulin-like growth factor I (IGF-I) levels, as it is generally accepted that IGF-I is the mediator of the growth-promoting activity of GH. With this brief background I would like to pose and respond to three questions:

• What is the origin of the concept that IGF-I has an important role in mediating growth?
• What is the specific contribution of GH or IGF-I in promoting growth?
• Might GH plus IGF-I work synergistically, such that their combined effects exceed the sum of their individual contributions?

Origin of the role of IGF-I

The assigned role of IGF-I as the mediator of GH’s growth promotion had its origins in the somatomedin hypothesis, first proposed by Daughaday and Salmon. Briefly, they noted that in using an in vitro assay to assess the incorporation of ³⁵S into cartilage rings, GH alone appeared to have no direct effects, whereas prior injection into hypophysectomized rats restored the ability of their serum to promote ³⁵S incorporation in a dose-dependent manner. The term “sulfation factor” was later replaced with the term “somatomedin” — ie, the mediator of somatotropin, also known as GH — because the serum of GH–treated animals promoted the incorporation of other factors such as ³H thymidine. Sulfation factor did not adequately cover the various aspects of growth-promoting activity.

Mark A. Sperling

Working independently, others discovered that growth-promoting activity similar to that of insulin persisted even after saturating antibodies to insulin removed all measurable insulin. This nonsuppressible insulin-like activity, when purified, was shown to be identical to somatomedin C and the substance termed IGF. IGF-I — together with its binding protein IGFBP-3 and the acid label subunit — are the terminal steps in the GH signaling cascade. Most of the circulating IGF-I results from GH signaling in the liver, which releases IGF-I into the circulation. However, in response to GH, IGF-I is also produced in other tissues in which IGF may exert autocrine/paracrine effects to promote growth.

To assess the contribution of each compound on growth, researchers deleted the individual genes or those of their receptors in the germ line of mice. The results of these mice studies suggested that about 35% of total growth could be attributed to IGF-I alone, 14% to GH alone and 34% to their combined effects — leaving about 17% of growth as “non-GH or non- IGF-I.” These mice data were later supported by data in humans treated with IGF-I for severe IGF-I deficiency, secondary to defects in GH receptors and their signaling cascades, as seen in patients with Laron syndrome. These patients are not restored to near-normal height unlike patients with GHD, who are capable of catch-up growth to normal height when treated with GH. Moreover, hypophysectomized rats have greater growth when treated with combination GH plus IGF-I compared with either hormone alone.

Thus, there are valid reasons to consider the potential benefits of treating children with apparent partial defects in GH signal transduction with both GH plus IGF-I. Such a study has indeed been undertaken, and preliminary results are encouraging.

Investigational use of GH plus IGF-I

At the 8th Joint Meeting of the Lawson Wilkins Pediatric Endocrine Society/European Society for Pediatric Endocrinology in June, George Bright, MD, presented the preliminary results of a phase-2, randomized, open-label, active treatment, controlled trial of recombinant human GH (rhGH) and recombinant human IGF-I (rhIGF-I) combination therapy in prepubertal children with short stature associated with low IGF-I.

The primary objective was to assess the safety and efficacy of GH/IGF-I combination therapy compared with GH alone in children with short stature known to have low IGF-I values but normal GH secretion in response to standard stimulation tests. Researchers assigned 106 prepubertal children to one of four treatment groups, each consisting of about 26 children. Group A was treated with daily GH 45 mcg/kg. Groups B, C and D were assigned the same dose of daily GH plus escalating doses of IGF-I at 50 mcg/kg, 100 mcg/kg or 150 mcg/kg. The children had never been treated with GH or IGF-I.

All children had short stature (≤–2 standard deviation score), serum IGF-I levels were <–1 SDS and the maximum stimulated GH level was >10 ng/mL. Children had no other associated illnesses such as hypothyroidism, chronic inflammation or renal disease as documented by history, physical exam and appropriate lab testing. Researchers examined height, weight and other indices of growth at two, four, 13, 26, 39 and 52 weeks. About one-third (n=36) completed the first year so that some estimate of efficacy was ascertained.

In the 36 first-year completers, first-year height velocities were about 9 cm in the GH-only group (n=11) and clearly higher in the children treated with GH plus IGF-I 150 mcg/kg. However, all groups treated with GH/IGF-I appeared to exceed the average growth velocity of the group treated with GH only. The mean first-year height velocity was 9.2 cm per year with GH alone; 10.4 cm with GH plus IGF-I 50 mcg/kg; 10.7 cm with GH plus IGF-I 100 mcg/kg; and 12.1 cm with GH plus IGF-I 150 mcg/kg. These improved growth velocities were reflected in a recovery of the mean first-year height SDS in the same rank order as the growth velocities. Although IGF-I levels achieved are not mentioned in this preliminary report, the dose of IGF-I was reduced if the IGF-I SDS exceeded 4; seven such patients were identified among the group treated with 100 mcg/kg or 150 mcg/kg per day. The first-year height increment markedly exceeded the first-year bone age increment, indicating that growth was not at the expense of bone maturation.

Among the entire group (n=106), there were four serious adverse events, and three were in the same patient who discontinued therapy. The other patient developed transient papilledema considered to be drug-related and temporarily discontinued therapy with no further adverse events when therapy was restarted. One patient withdrew from the study because of noncompliance, and four others withdrew because of adverse events, including urticaria, alopecia and a syndrome not considered to be drug-related. Tonsillar hypertrophy, a concern in patients with Prader-Willi syndrome treated with GH, was not observed in any patient treated with IGF-I. Transient abnormalities in liver enzymes were noted, but all returned to normal.

The study was sponsored by Tercica, a subsidiary of Ipsen.

Promising data

In summary, the interim results of the aforementioned recent investigation of GH plus IGF-I in children with low IGF-I levels suggested a significant increase in first-year height velocity. Further, researchers reported favorable increments relative to bone age and generally mild adverse events. However, with two patients who developed transient papilledema likely secondary to intracranial hypertension, due caution is warranted — even though both patients temporarily stopped therapy and were able to resume therapy without recurrence of papilledema. The trial is slated for an additional two years of observation, so adverse events will continue to be monitored carefully. Final analysis of patient outcomes and adverse events will occur when each patient has completed three years of treatment.

These are encouraging preliminary findings, and the final analysis for efficacy and extent of adverse events will be awaited with great interest. Notably, of the four adverse events for hypoglycemia, either as a reported symptom or a decreased glucose reported by the researchers, one occurred with GH alone and three with high-dose IGF-I. However, none of the patients had documented hypoglycemia of <50 mg/dL, a limiting factor and commonly observed finding in patients treated solely with IGF-I for GH receptor defects such as Laron dwarfism. Likewise, no patient reported signs or symptoms of diabetes or hyperglycemia.

Thus, combining GH plus IGF-I appears to amplify or potentiate the effects of each hormone and blunts some of their serious adverse events as previously noted for each hormone when assigned individually.

Paradigm shift in treatment

These human data complement mice data that have shown that near-total suppression of circulating IGF-I derived from the liver can be compensated by increased circulating GH, which must be acting on the growth plate either directly or by producing local IGF-I for paracrine-autocrine effects.

However, the GH dosages required to maintain normal growth are four to fivefold higher compared with normal physiological circumstances, and these high GH concentrations exert catabolic effects with increased lipolysis and circulating free fatty acids, hepatic steatosis, induction of insulin resistance, compensatory hyperinsulinemia and abnormal carbohydrate tolerance. It could be proposed from these animal studies that nature evolved a complementary mechanism to maintain growth via a substance that acts as a “second messenger” from GH to augment the growth-promoting effects of GH while restraining and modulating its catabolic effects.

These principles would remain valid in treating humans with short stature as a result of inadequate IGF-I production and termed “primary IGF-I deficiency,” a concept not fully accepted by all researchers. Nevertheless, this groundbreaking study may represent a paradigm shift in the treatment of some children with short stature. We await the final outcome with great interest.

Mark A. Sperling, MD, is a Professor in the Department of Pediatrics at the University of Pittsburgh and Children’s Hospital of Pittsburgh as well as a member of the Endocrine Today Editorial Board.

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