(From the December 2014 Research Now)
After nearly three decades of data collection, endocrinologist Juan F. Sotos, MD, of Nationwide Children’s Hospital has published the first compelling evidence that children with idiopathic short stature can achieve normal adult height with increased doses of recombinant human growth hormone. The study, published in the International Journal of Pediatric Endocrinology, is also among the few to analyze and detect differences in treatment outcomes between children with non-familial versus familial short stature.
Controversy regarding the use of rhGH for children with idiopathic short stature (ISS) has long included a cost-benefit debate. Historically, rhGH doses ranged from 0.16 to 0.26 mg/kg/week for children with ISS, and average height improvements hovered at about 4 cm. A few small studies have indicated that the height benefit may be dose dependent, but the risks and benefits of increased rhGH doses for these patients have not been carefully studied until now.
“We started this in 1988, treating children with 0.20 mg/kg/week of growth hormone,” says Dr. Sotos, who is the former chief of the Section of Endocrinology, Metabolism and Diabetes at Nationwide Children’s. “When I saw that the children didn’t respond as well as I would like, I increased it to 0.30 mg/kg/week.”
With the collaboration of his research associate, Naomi Tokar, Dr. Sotos performed a retrospective analysis of 123 of his patients with ISS at Nationwide Children’s and compared them to 305 historical controls from nine other studies. They also assessed non-familial short stature, familial short stature, normal puberty and delayed puberty subgroups to assess any differences in height attainment based on these factors.
Among study participants, approximately 20 percent were lost to follow-up, all of whom had been responding positively to treatment. Of the 88 children included in the final analysis, mean adult heights for males and females were 0.71 and 0.65 standard deviations lower than average, respectively, a significant improvement over starting mean heights of 2.58 and 2.71 standard deviations below average. Male participants grew an average of 9.5 cm and females an average of 8.6 cm more than untreated ISS controls from nine randomized and nonrandomized studies available in the literature.
“Growth hormone treatment significantly improved the adult height of children with ISS, sometimes with an improvement of up to 4 inches,” Dr. Sotos says. “Other studies had only modest benefits but used doses of 0.16 to 0.26 mg/kg/week, which may not have been adequate. Our experience was quite positive, though, with doses of about 0.32 mg/kg/week of rhGH.”
Final adult height and total height gain of children with non-familial short stature were significantly greater than those obtained by children with familial short stature. No difference was observed between normal and delayed puberty groups, except between non-familial and familial short stature participants.
“When you do a randomized study and don’t know whether participants have familial short stature or not, you lose some of the value of the study,” Dr. Sotos says. “Those with familial short stature are usually shorter at the end and respond less to growth hormone, and no one has proven that before except for in two small studies.”
Another aspect of the controversy over rhGH among children with ISS involves safety. Although the doses of rhGH were within approved ranges used to treat other conditions in children, such as growth hormone deficiency, Dr. Sotos and Tokar analyzed all children’s IGF-1 levels before, during and after treatment due to concerns that high IGF-1 levels are associated with future cancer. Less than 9 percent of the study participants had an IGF-1 value that exceeded the normal range even a single time during rhGH treatment, remaining essentially within the expected levels for their stages of puberty.
“Growth hormone is remarkably safe,” says Dr. Sotos, who is a professor of pediatrics and the former director of the Division of Endocrinology & Metabolism at The Ohio State University College of Medicine. “And this is not a ‘high’ dose — it’s what is used for other conditions. It’s just higher than what was used in the past for ISS.”
Although Dr. Sotos’ sixty-three year career in medicine is coming to an end, he is hopeful that this contribution to the literature will help other endocrinologists in the treatment of their patients with ISS.
“Here is the evidence that increased rhGH doses result in normalization of the heights during childhood and normal adult height, the main two aims of treatment,” Dr. Sotos says. “Treat your patients.”
Sotos JF, Tokar NJ. Growth hormone significantly increases the adult height of children with idiopathic short stature: comparison of subgroups and benefit. International Journal of Pediatric Endocrinology. 2014 July, 2014(1):15. [Epub ahead of print.]