In taking care of sick patients, clinicians have two goals: treating the disease and treating the symptoms. In the case of an infection or a chronic illness, accomplishing this dual purpose is relatively straightforward. But what about when the symptom is something more complicated than pain or nausea? Some genetic disorders carry the consequence of short height, a condition that may have more serious social effects than medical. But clinicians are nevertheless finding new ways to “treat” short height, helping children approach, if not fully reach, the size of their peers.
One genetic syndrome that carries the symptom of short stature is Turner syndrome, the result of a missing or incomplete X chromosome that occurs in 1 in 2,000 female births. In addition to some physical and reproductive abnormalities, Turner patients grow to an average of about 4-foot-7, several inches below the typical height for an adult female. Since 1996, the FDA has approved the use of growth hormone to help Turner patients achieve a closer-to-normal height, and the treatment, while very expensive, has achieved some success. But a new study finds that a second hormone, once thought to stunt growth rather than promote it, might be a useful additive in the treatment of short stature.
Estrogen is prescribed for a variety of medical uses, such as birth control, hormone replacement during menopause, but also as a suppressor of growth in teenage girls. However, the doses of estrogen given via pills or patches are much higher than what the body normally releases into the bloodstream. Some clinicians, including Robert Rosenfield, professor emeritus of adult and pediatric endocrinology, believe that these lower doses of estrogen may actually promote growth, particularly in Turner girls who have a deficiency of the hormone. But many doctors have shied away from giving Turner girls estrogen, he said.
“It’s obvious that normal girls have a growth spurt, and it turns out to be due to estrogen,” Rosenfield said. “But because of this long history of estrogen being seen as a growth inhibitor, people have delayed given estrogen in Turner syndrome until girls were maybe 14 or 15 years old because they didn’t want to rob girls of the growth-promoting benefits of hormone treatment.”
That theory was put to the test in a long-running and controversial study published last week in the New England Journal of Medicine. Nearly 150 girls with Turner syndrome were divided into different height-treatment groups: growth hormone alone, estrogen alone, growth hormone and estrogen, or placebo (this fourth group created some of the controversy, as the girls were not aware that they were receiving no treatment). The treatments were started when the girls were as young as 5 years old until their growth slowed in their teens, signaling that they had reached their adult height.
Between 1987, when the study began, and today, when the study was finally completed and published, the use of growth hormone in Turner girls has become accepted and approved. In fact, as far as growth hormone use goes, the good news of this study was no news, as the effect of GH alone on height was right in line with other, less rigorous studies conducted in Turner girls. The average size of that effect was not staggering: about 5 centimeters, or 2 inches, over the 7 years of treatment.
A more novel finding of the study was to clarify the benefit of estrogen in treating girls with Turner syndrome, Rosenfield said (and wrote about in an NEJM editorial with Leona Cuttler of Case Western Reserve University). In the group that received both low-dose estrogen and growth hormone, the effect on height was slightly larger – about 2 cm more. Despite the modest enhancement, the result also confirmed that low-dose estrogen does not interfere with growth hormone’s effects, and suggests that estrogen can be safely given to Turner girls earlier without concerns about stunting growth. That new information clears the way for benefits beyond height, as giving low-dose estrogen to Turner girls earlier will accelerate sexual development and improve bone strength.
“There’s a lot yet to be learned and this recent paper is one step in trying to optimize the use of estrogen,” Rosenfield said. “If it doesn’t interfere with and actually might enhance growth, this might allow girls to get their growth over with earlier, and that way not need growth hormone for so long. Therefore, we are reducing expenses and discomfort, and improving, to some extent, quality of life issues.”
A secondary finding might be to again temper expectations about the current ability of clinicians to manipulate height. Though growth hormone has been approved by the FDA for use in treating “idiopathic short stature” (essentially, non-disease-related shortness), that use has remained controversial due to its high cost (~$35,000 per centimeter gained). The new well-controlled study, in a population that does have a genetic syndrome with known hormonal effects, reinforces the mild successes of treating height and the decisions that creates for parents and patients where shortness is not a symptom, Rosenfield said.
“The biggest problem is in that in [idiopathic short stature] kids, and even in Turner, the amount of growth you get is modest. Parents come to us to this day thinking growth hormone is going to be a magic bullet that will make their child grow to meet their fondest expectations,” Rosenfield said. “But what we tell our patients is to ask themselves whether the treatment is worse than the ‘disease.’ They often perceive their short stature is a big handicap, but is it worth a shot a day and a lot of money?”
Cuttler L, & Rosenfield RL (2011). Assessing the value of treatments to increase height. The New England journal of medicine, 364 (13), 1274-6 PMID: 21449792
Ross JL, Quigley CA, Cao D, Feuillan P, Kowal K, Chipman JJ, & Cutler GB Jr (2011). Growth hormone plus childhood low-dose estrogen in Turner’s syndrome. The New England journal of medicine, 364 (13), 1230-42 PMID: 21449786