Adding ultralow-dose estrogen to growth hormone therapy in young girls with Turner’s syndrome improves adult height attainment and might provide additional neurocognitive and behavioral benefits, according to a report in the March 31 issue of the New England Journal of Medicine.
Carefully individualized ultralow-dose estrogen, given before puberty, appears to have a modest synergistic effect with growth hormone in promoting height velocity. Reportedly, some patients also have shown improvements in nonverbal processing speed, motor performance, verbal and nonverbal memory, and self-image with the dual therapy, said Dr. Judith L. Ross of Thomas Jefferson University, Philadelphia, and her associates.
The purpose of their study was twofold: to provide objective evidence from the first randomized, double-blind clinical trial that the accepted practice of giving growth hormone to girls with Turner’s syndrome in mid-childhood improves their markedly short stature, and to determine whether ultralow-dose estrogen at this age is beneficial or detrimental to height attainment.
Even though estrogen deficiency in Turner’s syndrome begins in infancy, "common clinical practice has been to postpone estrogen-replacement therapy until the mid-teens because of the widely held view that estrogen reduces height by accelerating epiphyseal fusion," the investigators noted.
Their findings suggest that to the contrary, this practice of delaying estrogen therapy "should be reconsidered."
"Although estrogen replacement during mid-childhood (prepuberty) may seem counterintuitive, this approach has a physiological rationale: the normal mid-childhood ovary is not entirely quiescent – plasma estradiol concentrations in healthy prepubertal girls, albeit low, are up to eight times as high as those in prepubescent boys," Dr. Ross and her colleagues said.
The study involved 149 girls aged 5-13 years who had Turner’s syndrome confirmed by karyotyping, breast development at Tanner stage 1-2, and height at or below the 10th percentile of that in the general population. The study subjects were enrolled between 1987 and 1996 and were followed through 2003.
The patients were randomly assigned to receive placebo injections plus oral estrogen (40 subjects), growth hormone injections plus oral placebo (35 subjects), growth hormone injections plus oral estrogen (35 subjects), or oral placebo plus placebo injections (39 subjects). They were assessed at 6-month intervals until they reached their adult height, which was defined as an annualized height velocity of less than 1.5 cm per year, and were assessed again approximately 1 year after completing the protocol.
Girls who received active growth hormone injections achieved significantly greater height than did those who received placebo injections, by approximately 5 cm. The height gain was even greater for girls given both active growth hormone and active estrogen, by an additional 2.3 cm.
Moreover, 79% of the girls who received both growth hormone and estrogen achieved significant gains in height, compared with only 65% of the girls who received growth hormone alone, 32% of the girls who received estrogen alone, and 15% of the girls who received double placebos, Dr. Ross and her associates wrote (N. Engl. J. Med. 2011;364:1230-42).
Serious adverse events were reported in 27 patients, including gynecologic disorders, pain, scoliosis, and thyroid disorders. However, "there were no new or unexpected safety findings with respect to growth hormone or estrogen treatment in this study," they added.
The researchers noted that, because this study was begun in the 1980s, the growth hormone regimen "may be considered suboptimal by current standards." The dose they used was 20% lower than the currently approved dose, and the three-times per week injection schedule they used is less effective than the daily injections that are currently recommended.
Similarly, the doses of estrogen that were deemed "ultralow-dose" 20 years ago when the study began, would now be considered excessive. At the time, "we aim[ed] to approximate the estrogen milieu in healthy prepubertal girls." However, it is now known that even lower doses would "minimize premature pubertal development and undue skeletal maturation."
The investigators emphasized that some girls with Turner’s syndrome don’t need estrogen supplementation, at least initially, because pubertal development can sometimes occur spontaneously. Approximately 13% of the girls in this study who received oral placebo instead of oral estrogen showed spontaneous breast development.
Taken together, the study findings demonstrate that "a regimen combining carefully individualized childhood estrogen replacement with growth hormone ... has the potential not only to optimize adult height but also to provide the neurocognitive and behavioral benefits of early estrogen administration," Dr. Ross and her colleagues said.