This randomized trial provides objective evidence concerning the efficacy and safety of growth hormone treatment initiated in mid-childhood for short stature associated with Turner’s syndrome. As compared with placebo, growth hormone treatment given at a dose of 0.1 mg per kilogram three times per week increased adult height by approximately 5.0 cm over an average period of 7.2 years. Data on adult height were not available for 39% of the study participants, an observation that reflects the long and complex nature of the study. However, a prospectively planned repeated-measures analysis of the intention-to-treat population showed treatment effects that were highly consistent with those in the adult-height analyses, indicating the robustness of the efficacy data.
There are probably multiple reasons for the somewhat smaller gain in height in our study than in some previous studies.5–13,35,36
Most previous studies have used either historical controls or the patient’s own baseline predicted or projected height5,8,10,11,13
to assess the treatment effect, possibly leading to systematic errors in the efficacy estimates.35
In addition, the growth hormone regimen in our study, which was designed in the mid-1980s, may be considered suboptimal by current standards. We used a dose of 0.3 mg per kilogram per week, which is 20% lower than the currently approved dose for children with Turner’s syndrome (0.375 mg per kilogram per week), and the thrice-weekly injection schedule in our study is less effective than daily administration.36
This difference in injection frequency may explain the greater mean height gain (7.2 cm during an average of 5.7 years) in a randomized, open-label study (the only prior study to include an untreated control group whose members were followed until they reached adult height) in which the total weekly dose of growth hormone given in divided doses 6 times per week was the same as in our study.12
Our results showed a trend toward a synergistic growth benefit from childhood low-dose estrogen combined with growth hormone, as indicated by the greater height gain in the growth hormone–estrogen group than in the group given growth hormone alone and by the lack of height gain in the group that received childhood low-dose estrogen without growth hormone. Because differences in the pubertal induction regimen initiated after the age of 12.0 years were minor (owing to protocol-defined individualization of doses), the between-group difference (growth hormone–estrogen vs. growth hormone alone) appears to have resulted from the childhood treatment regimen administered between 5.0 and 12.0 years of age — a finding that is consistent with our original hypothesis that treatment with a sufficiently low dose of estrogen would optimize growth in girls with Turner’s syndrome.24
The modest synergy observed between growth hormone and ultra-low doses of estrogen in childhood is not explained by differential effects of these two agents on systemic IGF-1, because the mean IGF-1 concentrations were similar throughout the study in patients treated with growth hormone plus childhood estrogen and those treated with growth hormone alone. Rather, the synergy might be due to a local increase in responsiveness to IGF-1 or growth hormone mediated by ultra-low estradiol concentration acting directly at the skeletal growth plate.37
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 prepubertal boys.38,39
Furthermore, low-dose estrogen administration in childhood has beneficial effects on cognition and self-image in patients with Turner’s syndrome, as reported previously in a subgroup of patients from this study.20,21
Nonverbal processing speed, motor performance, and verbal and nonverbal memory were significantly better in estrogen-treated girls 5.0 to 12.0 years of age than in placebo recipients of the same age.20,21
In addition to the timing, the dosage, type, and route of estrogen administration appear to influence its tissue-specific effects.40,41
We previously reported differential effects of varying doses of estrogen with respect to linear growth, vaginal maturation, and IGF-1 production.24
In the present study, we used an ultra-low-dose estrogen regimen derived from the initial study,24
aiming to approximate the estrogen milieu in healthy prepubertal girls. However, because our study was designed more than 20 years ago, the estrogen regimen has some limitations as a guide to current therapy. The protocol-specified dosages were excessive for most girls, with dose reductions required to minimize premature pubertal development and undue skeletal maturation. Dosage individualization based on protocol-defined criteria was a unique aspect of the present study; finding the lowest beneficial estrogen dose for each patient is an important goal, not only to minimize premature feminization but also to avoid potential late deleterious effects. Finally, some girls with Turner’s syndrome do not require estrogen supplementation, at least initially, because spontaneous pubertal development may occur, as evidenced by breast development observed in 13% of girls who received oral placebo during the childhood phase of this study (see the Supplementary Appendix
In conclusion, this placebo-controlled trial shows that growth hormone treatment initiated at an average age of 9 years increases adult height in girls with Turner’s syndrome. Furthermore, the modest growth benefit observed with the combination of ultra-low-dose childhood estrogen replacement and growth hormone suggests that the practice of delaying estrogen therapy should be reconsidered. A regimen combining carefully individualized childhood estrogen replacement with growth hormone in girls with Turner’s syndrome has the potential not only to optimize adult height but also to provide the neurocognitive and behavioral benefits of early estrogen administration.