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Early Initiation of Growth Hormone Treatment Allows Age-Appropriate Estrogen Use in Turner’s Syndrome¹

Departments of Pediatrics, Baystate Medical Center Children’s Hospital and Tufts University School of Medicine (E.O.R.), Springfield, Massachusetts 01199; and Medical Affairs, Genentech, Inc. (S.L.B., J.B., L.P.), South San Francisco, California 94080

Address correspondence and requests for reprints to: Edward O. Reiter, M.D., Department of Pediatrics, Baystate Medical Center Children’s Hospital, 759 Chestnut Street, Springfield, Massachusetts 01199. E-mail: edward.reiter{at}bhs.org

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Because estrogen (E) accelerates skeletal maturation it can decrease final height attainable with GH therapy in girls with Turner’s syndrome (TS). Nonetheless, as age-appropriate E administration does have psychobehavioral benefits for such patients, we asked whether E treatment in TS could occur without adverse impact on final adult height if GH therapy were started at an earlier age. Near adult height (NAH) was assessed in 344 girls with TS, who had received both GH and E and were followed in the National Cooperative Growth Study database. The groups were divided into quartiles based on age at initiation of GH (2–10, 10–12, 12–14, and 14–18 yr). The longest total and E-free period of GH treatment occurred in the girls who had started treatment in the youngest quartile (mean age, 8.2 ± 1.5 (SD) yr); they were also exposed to E at the youngest age (12.7 ± 1.6 yr). Although the girls in the youngest group received E at an earlier age, they had a significantly greater increase (1.8 ± 0.8) in Lyon height SD score at NAH over Lyon predicted adult height than those in the oldest GH-treated group (0.8 ± 0.6), which first received E at 15.9 ± 1.3 yr. Multiple linear regression equations for gain in Lyon height SD score and in height (cm) showed greater increments with a longer period of E-free GH therapy. All four GH age groups had the same NAH, but the youngest quartile was youngest at NAH and likely still having more growth potential. Comparable data were found in 127 TS girls with spontaneous puberty. In conclusion, girls with TS starting GH at an early age have a greater gain in Lyon SD score at NAH compared with those starting later, even though they received E at a younger age. If GH therapy were started early, E treatment could be initiated at a younger, more age-appropriate time without compromising adult height.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
BECAUSE FINAL ADULT height in women with Turner’s syndrome (TS) is approximately 8 inches shorter than their normal peers in study populations worldwide, short stature is a substantial clinical problem (1, 2, 3, 4, 5). Accordingly, diverse treatment protocols, including GH and androgens or estrogens (E) or both, have attempted to alter this situation. Using more aggressive GH programs, recent studies have resulted in markedly greater increments over untreated patients’ adult height projections (6, 7, 8, 9). On the contrary, particularly when started soon after initiation of GH therapy or early in teenage, E administration has caused clearly diminished final height outcomes (10, 11, 12). Nonetheless, it is important to define treatment regimens that would permit age-appropriate E exposure in TS without impairment of final height so that the psychological benefits of E therapy could be realized (5, 13, 14). To address this problem, we examined near adult height (NAH) outcomes in 471 North American girls with TS who had started GH treatment as young as 2 yr; 344 of these girls received E therapy. The data suggest that beginning GH at a younger age, thus providing a longer period of E-free GH treatment, may allow earlier E administration without loss of adult height.

	Subjects and Methods

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The National Cooperative Growth Study (NCGS) is an observational registry of children treated with recombinant GH products manufactured by Genentech, Inc. (South San Francisco, CA). Methods of patient enrollment and data collection have been described elsewhere (15, 19). As of June 2000, there were 3876 girls with TS in the NCGS database; 3050 had not previously received GH, were prepubertal at the onset of GH therapy, and were treated for at least 6 months with GH. The mean dosage of GH was 0.33 ± 0.07 (SD) mg/kg per week. Four hundred seventy-one girls had reached NAH; 344 of these had received E treatment, whereas 127 (or 27%) had some degree of spontaneous pubertal development and no reported exogenous E treatment. E use was defined by the documentation of administration of any E on the NCGS data sheets. The age at onset of E exposure was determined as the last age that Tanner stage I breast development was noted on the NCGS report data sheet.

NAH is defined as the height at a chronological age and bone age of at least 14 yr with at least pubertal Tanner breast development stage IV or a chronological age of at least 18 yr and Tanner stage III breast development. Data on height are presented as height SD score(s) relative to American girls with TS (16). Growth during GH treatment is reported as TS-specific height SD score. Bone age data at baseline, read at the individual clinical centers, are available in only 68% (321) of the patients.

The Lyon projection method (17), which assumes that the adult height SD score of girls with TS will equal their height SD score when first seen, was used to predict what the subjects’ heights would have been, had they not been given GH. This method has been validated in the United States for patients with TS (16).

The patients were divided into quartiles based on the ages at initiation of GH treatment (Table 1). Summary statistics are presented as means ± SD. The Jonckheere-Terpstra nonparametric test (18) was used to test for monotone trend across the baseline age groups. Additionally, pairs of groups were compared with each other using two-tailed t tests. Pearson correlation coefficients are also reported. Multiple linear regression was used to evaluate gain in height (cm) and gain in the Lyon height SD score. Two types of possible covariates were considered: baseline covariates–age, height, Lyon height SD score, and predicted adult height (PAH); and treatment covariates–duration of GH therapy, duration of E-free GH therapy, duration of GH therapy + E, and the age at onset of exposure to E. Subsets of covariates that were of clinical interest and not highly co-linear (r, <0.6) were tested, and in each case the significant covariates (P < 0.05, with verification using both forward and backward elimination procedures) were retained in the models. In particular, baseline height was correlated (co-linear) with age, Lyon height SD score, PAH, duration of GH therapy, and duration of E-free GH therapy. Baseline age was correlated with height, duration of GH therapy, duration of E-free GH therapy, and age at onset of exposure to E. Duration of E-free GH therapy and duration of GH therapy were also correlated. As a result, baseline age, height, and duration of GH therapy were not further considered in the subsets of possible covariates.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

Girls who received E therapy

NAH data were available on 344 girls. Baseline characteristics and duration of GH therapy or exposure to E are shown in Tables 1–3. The test for trend across the baseline age groups was significant (P < 0.005) for all baseline characteristics and onset and duration of therapy. The girls in the youngest group (mean age, 8.2 yr) had a significantly (P 0.0009) shorter mean baseline height SD score than the girls in each of the three older groups. There were no significant differences in mean height SD score between any of the three older groups. Baseline bone ages in each of the four age groups were significantly different from each of the other groups (P < 0.0001). Girls in the youngest group had less bone age delay than the girls in the two oldest groups (P 0.03), and the girls in the oldest group had a greater bone age delay than the girls in the two middle groups (P < 0.0001). The mean mid-parental target height was 163.4 ± 4.4 cm (-0.06 ± 0.76 SD score; n = 269) and did not differ among the four groups (data not shown). The girls who started treatment in the youngest group had the longest total and E-free period of GH treatment (Fig. 1). They started E at the youngest age (12.7 yr). Both the duration of E-free GH (r = -0.72, P < 0.0001) and total GH treatment (r = -0.81, P < 0.0001) were highly correlated with age at onset of GH therapy.

View larger version (38K): [in this window] [in a new window]   Figure 1. The duration of E-free GH therapy is related to the age at onset of GH therapy (or baseline age) in 344 girls with TS treated with E (•) and in 127 TS girls () who had spontaneous pubertal development. Note that the girls who started GH at the youngest ages had the longest duration of GH therapy.

View larger version (42K): [in this window] [in a new window]   Figure 2. The change in Lyon height SD score (SDS) from baseline age to NAH is related to the age at onset of GH therapy (or baseline age) in 344 girls with TS treated with E (•) and in 127 TS girls who had spontaneous pubertal development (). Note that the girls who started GH at the youngest ages had the largest changes in the height SDS from baseline to NAH.

View larger version (41K): [in this window] [in a new window]   Figure 3. The change in Lyon height SD score (SDS) from baseline age to NAH is related to the duration of E-free GH therapy in 344 girls with TS treated with E (•) and in 127 TS girls who had spontaneous pubertal development (). Note that the girls who received GH for the longest E-free period had the largest changes in the height SDS from baseline to NAH.

Girls who did not receive E therapy

NAH data were available for 127 girls who did not receive exogenous E therapy. Baseline characteristics and duration of GH therapy or exposure to E are shown in Tables 1–3. The test for trend across the baseline age groups was significant (P < 0.04) for all baseline characteristics and for onset and duration of therapy. The girls in the youngest group had a significantly (P < 0.01) shorter mean baseline height SD score than the girls in the two oldest groups. Mean baseline bone age in each of the four age groups is significantly different from each of the other groups (P < 0.02). The girls in the oldest group (mean age, 14.1 yr) had a significantly larger bone age delay than the girls in each of the three younger groups (P < 0.02). The mean mid-parental target height was 163.2 ± 4.2 cm (-0.09 ± 0.72 SD score; n = 108) and did not differ among the four groups. The group starting GH at the youngest mean age had an over 2-fold greater GH time exposure than the oldest group, with both E-free GH (r = -0.65, P < 0.0001) and total GH treatment duration (r = -0.73, P < 0.0001) highly correlated with age at onset of GH therapy (Fig. 1). Mean age of pubertal onset in the youngest age group was 11.4 yr.

NAH results are shown in Table 4. The test for trend across the baseline age groups was significant (P < 0.0001) for age at NAH and gain over Lyon PAH. There was no trend for NAH itself and no differences between any of the baseline age groups for NAH. Mean gain in NAH SD score was not significantly different between the two older groups. Otherwise, each of the younger groups gained significantly (P < 0.04) more than each of the older groups. Gain in NAH (cm) over PAH was not significantly different in the two youngest groups. Otherwise, each of the younger groups gained significantly (P < 0.03) more than each of the older groups. Gain in height SD score by baseline GH starting age is shown in Fig. 2. Multiple linear regression results were similar to those for the girls receiving E therapy.

Those starting GH at a younger age also have a younger age at NAH (16.0 ± 1.5 yr) than those in the oldest group (18.2 ± 2.0 yr), so have more potential for further growth and GH therapy as noted for the girls who received exogenous E.

Contrasting the TS girls receiving exogenous E with those having spontaneous puberty (endogenous E exposure)

The baseline characteristics, duration of GH therapy or exposure, to E of the two patient populations are shown in Tables 1–3. Twenty-seven percent of the girls had evidence of spontaneous pubertal changes. Baseline age and bone age delay was greater (P < 0.03) in the girls receiving exogenous E. The age at initial exposure to E was significantly (P < 0.02) older in the exogenous E group than in the spontaneous pubertal girls in each of the GH age quartiles. Accordingly, the duration of E-free GH treatment was longer in the E-treated patients. The total years of exposure to GH were similar in both groups. A significantly (P = 0.0007) greater mean increment at NAH over PAH was seen in the E-treated girls, looking at aggregate data of the two groups (6.3 ± 4.9 cm vs. 4.6 ± 5.1 cm). However, the gains in NAH SD score over PAH SD score were similar in both the exogenous E and endogenous E groups.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We analyzed the NAH outcomes of 471 GH-treated TS patients, who either received exogenous E or underwent spontaneous puberty. Our data represent the uncontrolled experience of North American pediatric endocrinologists, who reported their GH treatment results to NCGS. This study expands on that of Plotnick et al. (19), who used data from NCGS ending nearly 4 yr before our present assessment. The NAH results are slightly lower than those reported by Rosenfeld et al. (8) in a similar North American population, which received a 17% greater GH dose in a study environment. The definition of NAH used for analyzing these data also may affect the perceived benefit of GH therapy. The criteria of chronological age and bone age as described above would underestimate adult height and, thus, yield relatively conservative data on the salutary effects of treatment with GH. Despite the fact that E administration was started at mean age 12.7 yr in the group that had started GH at the youngest age, in contrast to the mean age of 15.9 yr in the oldest GH treatment group, the absolute mean height at the time of assessment of NAH was the same. This occurred at a significantly younger mean age (16.6 yr) than in the oldest group (18.7 yr), suggesting that there would still be some height growth potential leading to an even greater increment over the Lyon prediction. The greater increment in height and in Lyon height SD score from baseline to NAH occurred in the youngest group that started with the greatest relative height deficit, presumably due to a referral bias of assessing the smaller patients at an earlier time.

The present data strongly suggest that initiation of GH treatment at a younger age, thus achieving a longer period of total GH exposure as well as a longer E-free treatment interval, is associated with a greater increment over Lyon height predictions. The significant correlation of height gain with E-free GH treatment years supports this interpretation. These data encourage the starting of GH at a younger age so that E treatment may be initiated at an age-appropriate time.

In patients who did not receive E treatment and who had varying degrees of spontaneous pubertal maturation, the gain in height correlated strongly with the duration of prepubertal GH treatment. Furthermore, the gain in Lyon height SD score was nearly 3-fold greater in the group that began GH at the youngest age in contrast to the oldest group. As in the E-treated TS group, the girls with spontaneous puberty in the youngest quartile of initiation of GH therapy had the longest time before onset of pubertal changes and the greatest increment of height over Lyon PAH. Mean age (11.4 yr) of spontaneous puberty was 4 yr younger in the girls who received GH at the youngest than in the oldest age quartile, but it was still about 1 yr later than in normal American girls. GH treatment does not accelerate the onset or tempo of puberty in GH deficiency, children with intrauterine growth retardation, or in idiopathic short stature (20, 21, 22, 23), and it also did not in those TS girls who were treated at a young age and for the longest duration. There are some quantitative differences, however, between the girls exposed to exogenous or endogenous E. The age of initial E presence was younger with spontaneous puberty than in those with exogenous E treatment (11.4 vs. 12.7 yr), so that the period of E-free GH therapy was generally briefer in the GH treatment groups in the girls with sufficient endogenous E production to begin puberty. The gain in PAH at the NAH measurement was greater in the E-treated girls than those with spontaneous puberty. In the multiple regression analysis, it was determined that the duration of E-free GH therapy was the strongest independent predictor of gain in Lyon height SD score even with adjustment for potential confounders such as baseline height SD score. The overall results do not differ from the report of Pasquino et al. (24), who found that mean final adult height in girls treated with exogenous E was 1.0 cm greater than in those with spontaneous onset of puberty. Data describing increases over PAH are not available in that study.

The ability of GH to accelerate growth in TS has been demonstrated in a number of reports (6, 7, 8, 9, 10, 11, 12, 19). In a randomized, controlled study of GH in the United States, girls who received GH and oxandrolone had a mean gain of 10.3 cm in adult height over the Lyon height prediction, whereas those receiving GH alone had a mean increment of 8.4 cm (8). In another arm of that study the addition of E to the GH regimen in girls younger than age 14 lowered the adult height from 150.4 to 147 cm. Several other recent studies (7, 9), using higher doses of GH, have shown even greater gains in adult height outcomes. Sas et al. (9), in a multicenter trial, using a GH dose of approximately 0.63 mg/kg per week (twice the present dose) for 4.8 E-free GH treatment years beginning at mean age 8.1 yr, had a gain of 16 cm over the modified Lyon projection. In their group receiving the same GH dose as our patients, a height gain of 12.5 cm was achieved by age 16 with 4.8 E-free GH treatment years starting at mean age 7.9 yr. The greater height increment in the former group was likely dose related; the greater growth in the dosage group comparable with ours may relate to slightly earlier initiation of GH treatment and better adherence to the regimen because of the study environment. Carel et al. (7), using 0.7 mg/kg per week in a group that received 5.1 E-free GH treatment years beginning at 10.2 yr, gained 10.6 cm over Lyon projections. Their conventional dose group (0.3 mg/kg per week) gained 5.2 cm with 3.0 E-free GH treatment years starting at 11 yr. The substantial variations in GH dose, duration of E-free GH treatment years, age of initiation of GH and E administration, as well as population and parental adult heights, presumably account for the differences in GH-induced growth increments.

Along with data from the recent controlled studies (7, 8, 9), our findings support the concept that starting GH therapy at a younger age, thus allowing a longer period of E-free GH treatment, will permit initiation of E therapy at an age-appropriate time of approximately 11–12 yr. In a mathematical model developed and validated by Ranke et al. (25), youth also was correlated inversely with growth during the first 4 yr of GH treatment in TS, but timing of E therapy did not have a significant impact during that period. The demonstration (26, 27, 28) that significant growth retardation (nearly -3 SD) is already present by age 3 yr suggests that TS is a diagnosis to be considered in assessment of very young girls with growth failure and that early GH treatment would be appropriate. Although disputed, age-appropriate youthful E treatment may promote appropriate bone mineral accrual (29, 30, 31). We await data from larger numbers of girls with TS followed internationally (19, 32), in whom GH treatment has been started between 2 and 6 yr of age, permitting 6–10 yr of E-free GH years. E treatment in such a population could surely be able to be started by ages 11–12. Growth and psychosocial outcomes in those girls will be important to assess.

	Footnotes

 
¹ Presented in part at the 5th International Turner Syndrome, Naples, Italy, 2000.

Received December 11, 2000.

Revised January 26, 2001.

Accepted February 2, 2001.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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