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Prepubertal Growth Hormone + Ultralow-Dose Estrogen for Turner’s Syndrome
Major Finding: Girls with Turner’s syndrome who received growth hormone injections grew 5 cm taller than did those who received placebo injections...
ORLANDO – The dosing of growth hormone based on insulinlike growth factor–I levels is an effective strategy to help children with idiopathic short stature, based on a study that revealed significant gains in height velocity compared with controls.
"The most rational, cost-effective, and easy approach is to dial up the growth hormone [dosage] to achieve IGF-I to the upper 1 standard deviation of normal," Dr. Pinchas Cohen said. "This represents the optimal approach to this population at this time, in my mind."
The latest news regarding growth hormone is not about new agents or formulations, but about dosing strategies that more effectively deliver existing therapies, Dr. Cohen said at a symposium on IGF-I, growth hormone, and ghrelin/GHS sponsored by the University of South Florida.
Dr. Cohen and his colleagues randomized 114 children with varying levels of IGF-I deficiency to either treatment or observation. Participants were aged 3-15 years and were prepubertal; 70% were boys. The treatment group had their growth hormone dosage increased to target 1 standard deviation above the norm for IGF-I at 30, 90, 180, and 270 days, and at 1 year.
The growth hormone dosage was titrated up at each visit, unless patients were in the 66th- to 99th-percentile range. "The dose we achieved at the end of the study was quite moderate," Dr. Cohen said, "somewhat less than 60 mcg/kg per day." It was higher than the Food and Drug Administration–recommended dosage at the time, he added, although the current FDA-approved dose for idiopathic short stature (ISS) is 67 mcg/kg per day.
That resulted in a decrease in the IGF-I standard deviation score from a mean at the low range of normal (or sometimes even lower than that) to just above the mean at the end of the study. In contrast, "IGF-I essentially stays the same over time" in controls, Dr. Cohen said.
With treatment, the height velocity increased at each visit. By 90 days, the treated group of children had a growth velocity of about 10 cm/yr, and "they pretty much maintained that throughout the first year," compared with essentially no change in the control group, Dr. Cohen said. The difference was statistically significant.
In general, a dramatic rise in growth velocity at 3 months with conventional growth hormone treatment decreases somewhat at 1 year, Dr. Cohen said, but that was not the case in the current study. "Based on IGF-I dosing, we are preventing that expected small decline in the growth velocity by accelerating the dose to meet the IGF target requirement. This may be an interesting, unexpected advantage of this dosing strategy," said Dr. Cohen, professor of pediatrics at the University of California, Los Angeles, and chief of endocrinology at the Mattel Children’s Hospital UCLA.
Dr. Cohen also expressed the data in terms of gains in standard deviations of height.
"Patients start out at a mean height just below –2.5 [standard deviations], with no change at all in the untreated group and a nice rise in the growth in the treated group," Dr. Cohen said.
If patients are divided into subgroups based on their basal IGF-I –those with substantial IGF-I deficiency vs. those with normal IGF-I deficiency – "you can see [that] the degree of height gain during the study is essentially identical." Thus, in ISS patients with variable degrees of IGF deficiency, "the baseline IGF-I does not influence the response to growth hormone therapy," said Dr. Cohen, who is also the codirector of the diabetes and endocrinology research center at the University of California, San Diego/UCLA.
The study (NN2147) will be submitted for journal publication in 2011, Dr. Cohen said. He added that the findings validate and confirm his previous studies on IGF-based dosing (J. Clin. Endocrinol. Metabl. 2010;95:2089-98; J. Clin. Endocrdinol. Metab. 2007;92:2480-6).
Dr. Cohen disclosed that he is an adviser to Novo Nordisk and the Ipsen Group; is a consultant to Theratechnologies Inc. and Teva Pharmaceuticals; and receives research grants and support from Amgen, Eli Lilly, and Genentech.