Introduction: In the randomized “Toddler Turner” study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters. Methods: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups. Results: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>−2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = −0.30; p = 0.016]). No new safety concerns arose. Conclusion: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood.

The growth failure that characterizes Turner syndrome (TS) results primarily from haploinsufficiency of the SHOX gene located on the short arm of the X (and Y) chromosome [1‒6] and is progressive from infancy to adulthood. The average length of full-term babies with TS is approximately 0.7 standard deviations (SD) below the mean for the general population; average untreated height falls below −2.0 standard deviation score (SDS) by 4 years of age [7] and is below −3.0 SDS in adulthood [8, 9]. Average adult heights of large groups of untreated women with TS from various countries are around 143–146 cm, making them about 20 cm below the average heights of their unaffected countrywomen, and about 20 cm below their mid-parental (target) heights [8‒13]. Thus, prevention of growth failure and maintenance of height within the population normal range throughout childhood and into adulthood may be considered quintessential goals of care in girls with TS.

Growth hormone (GH) has been approved in the USA since 1996 for treatment of TS-associated short stature, based on studies conducted in the 1980s to 1990s, in which treatment was typically initiated around 9–10 years of age [14‒17]. Because height SDS declines with increasing age in untreated girls, those regimens employed the strategy of delaying estrogen replacement, often until the mid-to-late teen years, to maximize the time available for GH treatment [16, 17]. However, subsequent data revealed the importance of timely estrogen supplementation not only for feminization but for other aspects of health and well-being [18‒24]. Therefore, in addition to maximizing adult height, the current goals of GH treatment include normalizing stature during the prepubertal years to mitigate early physical and psychosocial barriers and to allow puberty to begin at a similar age to peers [25, 26].

In the randomized, controlled, multicenter “Toddler Turner” trial (parent study of the data reported here), 2 years of GH treatment initiated at an average age of 2 years stimulated significant catch-up growth, returning height to near-average in the preschool years and preventing the ongoing growth failure observed in the untreated controls [27]. However, after completion of the controlled trial, important questions remained regarding effects of very early GH treatment on timing and tempo of subsequent growth and pubertal maturation, adult height, and long-term safety. To address some of these gaps, children from the Toddler study cohort were invited to participate in a 10-year observational extension study, providing a unique opportunity to assess the long-term effects of very early GH treatment. Of particular interest was the possibility that girls who received early GH would attain heights comparable with peers by their early teen years, allowing pubertal development (either spontaneous or induced) at more physiological ages than typically had been achieved in studies published in the 1990s and 2000s.

Study Design

The data presented in this report derive from a long-term investigation (1999–2015) comprising 3 phases: the 2-year Toddler Turner randomized controlled trial (RCT); the informal off-study phase between completion of the Toddler study and entry to the Extension, referred to herein as the Inter-study period; and the 10-year observational follow-up referred to as the Extension study (Fig. 1a).

Fig. 1.

a Study flow diagram. Eighty-eight GH-naive girls with karyotype-proven TS were randomized at baseline of the 2-year Toddler study in a 1:1 ratio to GH treatment (GH group, n = 45) or non-GH-treated control (control group, n = 43). After completing the Toddler study, control subjects were offered 2 years’ complimentary GH during the Inter-study period in recognition of their 2 years of nontreatment during the controlled phase. The Inter-study period between the end of the Toddler study and beginning of the Extension study was of variable duration for individual subjects (2.6–6.7 years), depending on timing of departure from the Toddler study and entry to the Extension study. Of 88 Toddler study subjects, 69 entered the Extension study and were classified according to their original Toddler study treatment group as early treated (ET, n = 36; original GH group) or early untreated (EUT, n = 33; original control group). Fifty-one subjects attained NAH on study (ET, n = 25; EUT, n = 26). b Subject disposition in the Extension study. Of 88 Toddler study subjects, 69 entered the Extension study (safety population), 67 had at least 1 post-baseline visit (ITT population), and 51 attained NAH on study (defined as the first height measurement after height velocity was ≤2.0 cm/year or bone age was ≥14.5 years). One EUT subject who received no GH at any time was excluded from efficacy analyses. GH, growth hormone; TS, Turner syndrome; ET, early-treated; EUT, early-untreated; NAH, near-adult height; ITT, intent-to-treat.

Fig. 1.

a Study flow diagram. Eighty-eight GH-naive girls with karyotype-proven TS were randomized at baseline of the 2-year Toddler study in a 1:1 ratio to GH treatment (GH group, n = 45) or non-GH-treated control (control group, n = 43). After completing the Toddler study, control subjects were offered 2 years’ complimentary GH during the Inter-study period in recognition of their 2 years of nontreatment during the controlled phase. The Inter-study period between the end of the Toddler study and beginning of the Extension study was of variable duration for individual subjects (2.6–6.7 years), depending on timing of departure from the Toddler study and entry to the Extension study. Of 88 Toddler study subjects, 69 entered the Extension study and were classified according to their original Toddler study treatment group as early treated (ET, n = 36; original GH group) or early untreated (EUT, n = 33; original control group). Fifty-one subjects attained NAH on study (ET, n = 25; EUT, n = 26). b Subject disposition in the Extension study. Of 88 Toddler study subjects, 69 entered the Extension study (safety population), 67 had at least 1 post-baseline visit (ITT population), and 51 attained NAH on study (defined as the first height measurement after height velocity was ≤2.0 cm/year or bone age was ≥14.5 years). One EUT subject who received no GH at any time was excluded from efficacy analyses. GH, growth hormone; TS, Turner syndrome; ET, early-treated; EUT, early-untreated; NAH, near-adult height; ITT, intent-to-treat.

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Toddler Turner Study Period

The Toddler study was a 2-arm, parallel, open-label, multicenter RCT of the effect of 2 years of GH treatment (vs. no treatment) on linear growth of infants and toddlers with TS (11 US study sites; August 1999 to August 2003; NCT00406926) [27]. Inclusion criteria were karyotype-proven TS; age 9 months to 4 years; normal baseline urinalysis, hemoglobin, and TSH; and adequate thyroid hormone replacement for those with hypothyroidism. Exclusion criteria were presence of Y-chromosomal component in the karyotype if gonads were in situ, autosomal anomaly, systemic illness, or concurrent treatment that might influence growth. Eighty-eight eligible girls were randomized in a 1:1 ratio to either a GH treatment group (50 μg/kg/day Humatrope® [rhGH]; Eli Lilly and Company; n = 45) or an untreated control group (n = 43). Seventy-eight of the 88 subjects (89%) completed the 2-year study. The Extension study was not part of the original Toddler study protocol but was designed after completion of the primary study.

Inter-Study Period

The Inter-study period between the 2 protocol-defined phases of the study (Toddler and Extension) had no formal protocol. Subjects who had participated as Toddler study controls were provided with complimentary GH for 2 years after completing the original study, in recognition of their 2 years as untreated controls during the RCT; girls in the GH-treated group of the Toddler study were not provided with GH in the Inter-study period but were treated at the discretion of their physicians and families during this time. Because of varying departure dates/ages from the Toddler study and entry dates/ages to the Extension, the duration of each participant’s Inter-study period was variable.

Extension Study Period

The Extension study was a multicenter, 10-year (2005–2015; NCT00266656) observational study initiated 2 years after the last subject departed the Toddler study. The protocol was approved by local Ethics/Institutional Review Boards and informed consent/assent was obtained from parent(s)/legal guardian(s)/subjects according to local requirements. All Toddler study subjects were eligible to enter the Extension study whether or not they had completed the original trial, and GH was provided by the sponsor to all participants. Investigators were encouraged to follow the pubertal induction regimen described by Davenport [23], with initiation of low-dose transdermal estradiol (E2) at ∼11 years of age, followed by slow escalation of E2, addition of progestin after ∼3 years, and attainment of adult estrogen dosages after ∼4 years. Because of the observational nature of the Extension, all treatment decisions and dosing for GH and estrogen replacement were at the discretion of the investigators, local endocrinologists, and families.

Data Collection in the Extension Study

Data collected at Extension study baseline included historical information from the Inter-study period such as illnesses, GH and/or estrogen treatment, concomitant medications, physical examination, auxology, pubertal status, bone age and laboratory data. Data collected at annual Extension visits included medical history since last visit, occurrence of breast development and/or menarche, GH dosing and treatment adherence (missed injections in the week, 3-month period and 12-month period prior to each annual visit), concomitant medications, anthropometric measurements, physical examination, clinical assessment of Tanner breast and pubic hair stages, bone age X-ray results, laboratory data, and adverse event reports.

Efficacy Measures

Puberty was defined as presence of Tanner breast stage 2 or greater (≥B2). Because subjects were seen annually, Tanner stage B2 may have been missed in some girls, in which case Tanner stage B3 was used as the proxy for the start of puberty resulting in older estimated age at onset of puberty. Near-adult height (NAH) was defined as the first height measurement obtained after height velocity was ≤2.0 cm/year (in the absence of any additional growth-impairing process) or bone age was ≥14.5 years (assessed by 2 independent readers, blinded to treatment status). Last available height on study was the last height measured prior to subject departure from the study, which may or may not have been equivalent to NAH, as some subjects left before NAH and some continued after attainment of NAH.

Safety Measures

Targeted questions on case report forms were used to assess occurrence of the following prespecified adverse events: benign intracranial hypertension, diabetes mellitus or impaired glucose tolerance, ear infections, high blood pressure, hypothyroidism, neoplasia, pancreatitis, scoliosis, and slipped capital femoral epiphysis. Standard reporting of serious adverse events (SAEs) and non-serious, treatment-emergent adverse events, as defined by the US Food and Drug Administration, was also performed [28].

Fasting blood samples were drawn at each visit for central laboratory measurements of glucose, insulin, IGF-I, and IGFBP-3. In addition, HbA1c, oral glucose tolerance, and fasting lipids were measured at baseline and at ages ~10 and ~16 years and last visit.

Study Populations

For analytical purposes, subjects were designated as GH-treated if they received ≥6 months of continuous GH during any phase of the study. Based on their original treatment assignments in the Toddler study, subjects were classified into 2 groups as “early-treated” (ET group: those originally randomized to GH) or “early-untreated” (EUT group: those originally randomized to the non-GH-treated control group).

Three populations were defined for analysis: the safety population included all subjects who had a baseline visit in the Extension study, the intent-to-treat (ITT) population included all subjects who had baseline and at least 1 post-baseline Extension visit, and the NAH population was a subset of the ITT population that included all subjects who attained protocol-defined NAH (see Efficacy Measures) during study. One subject who received no GH at any time (45,X/46,XX karyotype, height at Toddler study entry +1.26 SDS [US female standards], and height at Extension study entry +1.56 SDS) was excluded from efficacy analyses.

Statistical Methods

The primary aim of the Extension study was to evaluate the long-term effect of GH treatment given during early childhood (i.e., starting ≤ 4 years of age), by comparing height SDS at NAH of girls who received 2 years’ GH in the Toddler study to those who were untreated during that period. To account for potential baseline differences between the ET and EUT groups, a between-group analysis of covariance (ANCOVA) was conducted for NAH, with Toddler study baseline age and baseline height SDS as covariates; results were considered significant at the 5% level using a 2-sided test (p < 0.05). Detailed description of power assessment for the primary analysis is provided in online suppl. material; see www.karger.com/doi/10.1159/000513788 for all online suppl. material.

Mean ± SD (or least squares mean/standard error for ANCOVA), median, minimum, and maximum (or range) are provided for continuous variables. Categorical variables are summarized as number (percentage). No power assessments were made for any analyses other than the primary, so p values are provided for a limited number of analyses and considered informational only; they should not be used to infer treatment effects or lack thereof. Factors associated with greater NAH were examined using Pearson correlations between NAH SDS and age at GH start, height SDS at GH start and duration of GH treatment. Height SDS values were calculated using US general population standards [29], and statistical analyses were performed using SAS version 9.1 or higher (SAS Institute Inc., Cary, NC, USA) and SPSS 24 or higher (IBM Corp., Armonk, NY, USA).

Longitudinal data from all 3 periods of the investi­gation are included in this report: the original 2-year randomized Toddler study, the informal Inter-study period (variable duration), and the 10-year Extension (Fig. 1a).

Demographics

Of the 88 eligible Toddler study participants, 69 (78%) entered the Extension study and comprise the safety population (ET, n = 36; EUT, n = 33); the remaining 19 girls either declined participation or could not be contacted (Fig. 1b and online suppl. material). Sixty-seven of 69 subjects in the safety population had at least 1 post-baseline follow-up visit and comprise the ITT population (ET, n = 35; EUT, n = 32); 51 subjects attained NAH on study (NAH population: ET, n = 25; EUT, n = 26). Among 67 girls in the ITT population, 60 (90%) were of Caucasian origin, 46 (69%) had 45,X karyotype, 11 (16%) had 45,X/46,XX karyotype, and 10 (15%) had other karyotypes.

Demographic characteristics of the Extension study ITT population at key time points are provided in Table 1 and Table 2. The ET and EUT groups were similar in age to each other at entry to the Toddler study (mean for combined groups, ∼1.9 years) and entry to the Extension study (mean for combined groups, ∼8.3 years; Table 1). The key difference between the groups was the age at initiation of GH: 1.9 ± 0.9 years for the ET group (i.e., at Toddler study entry) and 4.7 ± 1.8 years for the EUT group, most of whom started GH at the beginning of the Inter-study period (Table 2); because of their older age and longer period of nontreatment, the EUT group was substantially shorter than the ET group at GH initiation (mean, −2.2 vs. −1.4 SDS, Table 2). The 19 subjects who did not participate in the Extension were somewhat shorter at baseline and endpoint of the Toddler study than those who entered (see online suppl. Table).

Table 1.

Summary data by phase of study: ITT population

 Summary data by phase of study: ITT population
 Summary data by phase of study: ITT population
Table 2.

Treatment and growth parameters, GH start to GH endpointa: ITT population

 Treatment and growth parameters, GH start to GH endpointa: ITT population
 Treatment and growth parameters, GH start to GH endpointa: ITT population

GH Treatment Details and Growth Responses by Treatment Group (ET vs. EUT)

GH treatment durations and overall growth outcomes (GH start to Extension study endpoint) are summarized in Table 1 (by study period) and Table 2 (overall); Figure 2 illustrates mean height SDS values by treatment group at key time points, from Toddler study baseline (average age 1.9 years overall), to last height on study (average age 15.0 years). Treatment outcomes during each phase of the study and overall are summarized in individual sections below.

Fig. 2.

Mean height SDS from Toddler study baseline (TB) to Extension study endpoint (ITT population). The ET group is shown as filled circles with solid line (blue) and the EUT group as crosses with dashed line (red). For both groups, each point represents the mean age (X axis) and mean height SDS (y axis) for subjects in the ITT population at each key time point. Arrow marks the start of the Extension study. Horizontal solid blue line and dashed red line below the x axis represent the range of GH start ages for the 2 groups: ET, 0.8–4.0 years (entry to Toddler study); EUT, 1.7–9.9 years (during Inter-study or Extension period). The 5 horizontal dashed lines at the base of the figure represent the ranges of ages at each of the key time points for the combined groups (ET + EUT): Toddler baseline (TB), 0.8–4.0 years; Toddler endpoint (TE), 1.7–6.0 years; Extension baseline (EB), 6.1–11.1 years; puberty onset (≥B2), 7.8–16.0 years; GH endpoint, 11.4–18.4 years (excludes 3 girls who received no GH during the Extension). SDS, standard deviation score; ITT, intent-to-treat; ET, early-treated; EUT, early-untreated; GH, growth hormone.

Fig. 2.

Mean height SDS from Toddler study baseline (TB) to Extension study endpoint (ITT population). The ET group is shown as filled circles with solid line (blue) and the EUT group as crosses with dashed line (red). For both groups, each point represents the mean age (X axis) and mean height SDS (y axis) for subjects in the ITT population at each key time point. Arrow marks the start of the Extension study. Horizontal solid blue line and dashed red line below the x axis represent the range of GH start ages for the 2 groups: ET, 0.8–4.0 years (entry to Toddler study); EUT, 1.7–9.9 years (during Inter-study or Extension period). The 5 horizontal dashed lines at the base of the figure represent the ranges of ages at each of the key time points for the combined groups (ET + EUT): Toddler baseline (TB), 0.8–4.0 years; Toddler endpoint (TE), 1.7–6.0 years; Extension baseline (EB), 6.1–11.1 years; puberty onset (≥B2), 7.8–16.0 years; GH endpoint, 11.4–18.4 years (excludes 3 girls who received no GH during the Extension). SDS, standard deviation score; ITT, intent-to-treat; ET, early-treated; EUT, early-untreated; GH, growth hormone.

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Toddler Study Period (ITT Population)

During the Toddler study, all 32 EUT subjects were untreated, whereas all 35 ET subjects received 2 years of GH (50 μg/kg/day), resulting in a marked increase in mean height for the ET group (Fig. 2, TB to TE) and significant between-group height difference of 1.6 ± 0.6 SDS by ANCOVA (p < 0.001) [27]. Thus, at the end of the Toddler study, at ∼3.9 years of age, the ET group was on average >7 cm taller than the EUT group (Table 1).

Inter-Study Period (ITT Population)

Apart from the Toddler study itself, the Inter-study period (individual subject duration range, 2.6–6.7 years) was the time of greatest difference in growth between the ET and EUT groups. The beginning of the Inter-study period (end of the Toddler study) represented the start of 2 years’ complimentary GH for the EUT group, whereas it marked the completion of protocol-specified GH treatment for the ET group. According to the analysis criteria 26/35 (74%) ET subjects were designated as GH-treated during the Inter-study period, having received ≥6 months’ treatment overall in this period (Table 1). However, due to the variable and extended duration of the Inter-study phase, some ET subjects had delayed treatment restart or prolonged interruptions of treatment, and 14/35 (40%) subjects were untreated for ≥1 year (range, 1.9–6.4 years). As shown in Fig. 2 (TE to EB), these treatment lapses resulted in substantial post-GH catch-down growth for 11 subjects (average 0.9 SDS decline, range −0.3 to −2.2). In contrast to the substantial height SDS declines of ET subjects who were untreated or partially treated after completion of the Toddler study, the EUT group showed the typical catch-up growth of GH-naive subjects after starting treatment (average 0.6 SDS height increase; Fig. 2, TE to EB), as 26/32 subjects (81%) received GH for at least 6 months during the Inter-study period (Table 1). As a consequence of the divergent treatment and growth patterns during this period (catch-down growth of the ET group and catch-up growth of the EUT group), there was substantial narrowing of the between-group height difference, from ∼1.6 SDS (∼7 cm) at the end of the Toddler study (Fig. 2, TE) to ∼0.6 SDS (∼3 cm) at the start of the Extension (Fig. 2, EB).

Extension Study Period (ITT Population and NAH Population)

During the 10-year Extension study, 33/35 girls (94%) in the ET group and 31/32 girls (97%) in the EUT group received GH treatment for an average of 6.1 and 7.4 years, respectively (Table 1). Sixty of 67 subjects had already received at least 2 years’ GH treatment by the time they entered the Extension. Adherence to prescribed GH was generally fair to good: by parent estimate, 82–94% of subjects missed 0–2 prescribed injections per week in the 3 months preceding each annual visit; we assumed that the 3-month estimate would be reasonably representative of the full-year’s adherence.

Figure 2 demonstrates that the mean height SDS of the ET and EUT groups followed very similar trajectories from Extension study baseline (Fig. 2, arrow) to GH endpoint, with the ET group on average about 0.4–0.7 SDS taller than the EUT group throughout. Both groups showed a slight increase in height SDS between Extension baseline at mean age ∼8.3 years and ∼10.0 years of age, followed by a decline (mean ∼0.5 SDS) prior to the onset of puberty (≥ B2). Height SDS changes after the onset of puberty were small and the differences carried forward to NAH, when the ET group was younger and taller than the EUT group (mean: ET, 14.7 years, −1.3 SDS; EUT, 15.3 years, −1.7 SDS; Table 3).

Table 3.

Treatment and growth parameters, GH start to NAH and last visita: NAH population

 Treatment and growth parameters, GH start to NAH and last visita: NAH population
 Treatment and growth parameters, GH start to NAH and last visita: NAH population

Study as a Whole (Toddler Study Baseline to Extension Study Endpoint: ITT Group and NAH Group)

Overall, both treatment groups had positive outcomes over the prolonged duration of this study, maintaining average heights within the mid-to-lower part of the female reference population height range during GH treatment [29, 30]. Notably, at the start of GH treatment (as distinct from study start), the EUT group was substantially shorter than the ET group (−2.2 vs. −1.4 SDS; Table 2), because the EUT group had 2 years of progressive growth failure while untreated during the Toddler study (Fig. 2, TB to TE). Consequently, on average the EUT group remained shorter than the ET group at each time point from the preschool years to maturity (Fig. 2).

Although the EUT group was older than the ET group at the start and end of treatment (Table 2), the average total durations and GH dosages for the groups over the whole study were very similar (ITT population: ET: 11.0 years, ∼0.29 mg/kg/week; EUT: 10.8 years, ∼0.30 mg/kg/week). This similarity of GH exposure resulted in part from the lower rates of treatment in the Inter-study period for the ET group and their greater inconsistency of treatment after completion of the Toddler study (i.e., >6 months interruption over the whole course of the study: ET, 13/35 [37%] vs. EUT, 5/31 [16%]). In addition, because most EUT subjects began treatment as soon as possible after completing the Toddler study, 45% of these girls started GH by age 4 years and 84% started by age 6 (per protocol, 100% of ET subjects started GH by age 4 years).

For the NAH population, the combined-group mean NAH of ∼151 cm (−1.5 SDS) was attained at 15 years of age (Table 3). The primary efficacy analysis did not demonstrate a significant between-group height SDS difference at NAH when all subjects were included, as specified a priori (least squares mean ± SEM: ET, −1.35 ± 0.14; EUT, −1.56 ± 0.14; p = 0.30 by ANCOVA with age and height SDS at Toddler study baseline as covariates). The results were not affected by exclusion of the EUT subject who received no GH at any time (data not shown). One year after NAH (age 16 years), mean heights were only about 1 cm greater than heights at NAH, indicating that growth had essentially ceased (Table 3). Mean changes in height SDS from GH start to NAH or last last visit after NAH were small (Table 3) and were not appreciably different when the analysis was limited to subjects whose treatment was uninterrupted. The Kaplan-Meier analysis of age at NAH demonstrates a left shift of the curve for the ET group compared with the EUT group, indicating generally somewhat younger attainment of NAH (Fig. 3a).

Fig. 3.

Kaplan-Meier curves. a Chronological age at attainment of NAH (defined as 1st height obtained after height velocity ≤2.0 cm/year or bone age ≥14.5 years): the ET group (solid blue line) attained NAH earlier than the EUT group (dashed red line). Vertical tick marks above each curve represent ages at last observation of subjects who did not attain NAH on study. b Chronological age at attainment of breast development at or beyond Tanner stage 2 (≥B2): breast development occurred earlier for the ET group (solid blue line), than the EUT group (dashed red line) particularly after age 11.5 years. Vertical tick marks above each curve represent ages at last observation of subjects who did not attain breast development on study. NAH, near-adult height; ET, early-treated; EUT, early-untreated.

Fig. 3.

Kaplan-Meier curves. a Chronological age at attainment of NAH (defined as 1st height obtained after height velocity ≤2.0 cm/year or bone age ≥14.5 years): the ET group (solid blue line) attained NAH earlier than the EUT group (dashed red line). Vertical tick marks above each curve represent ages at last observation of subjects who did not attain NAH on study. b Chronological age at attainment of breast development at or beyond Tanner stage 2 (≥B2): breast development occurred earlier for the ET group (solid blue line), than the EUT group (dashed red line) particularly after age 11.5 years. Vertical tick marks above each curve represent ages at last observation of subjects who did not attain breast development on study. NAH, near-adult height; ET, early-treated; EUT, early-untreated.

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Subject-Level Outcomes (ITT Population and NAH Population)

Because of the known variation in outcomes of GH treatment among individual patients, we examined factors associated with greater NAH SDS for the Extension study cohort as a whole, irrespective of original Toddler study treatment group. There was a strong positive correlation between height SDS at GH start and NAH SDS (r = 0.78; p < 0.01; Fig. 4a), and a significant negative correlation between age at GH start and height SDS at GH start (r = −0.30; p = 0.016; Fig. 4b), indicating that height SDS declined with increasing age prior to start of treatment (i.e., untreated younger girls were taller for age than older girls). There was a negative but nonsignificant association between age at GH start and NAH SDS (r = −0.20; p = 0.17; Fig. 4c). There was no significant association between duration of GH treatment and either NAH SDS or change in height SDS from GH start to NAH.

Fig. 4.

Pearson correlations. a Height SDS at GH start versus height SDS at NAH (r = 0.78, p < 0.01). b Age at GH start versus height SDS at GH start (r = −0.30, p = 0.016). c Age at GH start versus height SDS at NAH (r = −0.20, p = 0.17). SDS, standard deviation score; GH, growth hormone; NAH, near-adult height.

Fig. 4.

Pearson correlations. a Height SDS at GH start versus height SDS at NAH (r = 0.78, p < 0.01). b Age at GH start versus height SDS at GH start (r = −0.30, p = 0.016). c Age at GH start versus height SDS at NAH (r = −0.20, p = 0.17). SDS, standard deviation score; GH, growth hormone; NAH, near-adult height.

Close modal

To evaluate attained heights of our study population in the context of the standard growth curve for girls without TS [30], Figure 5 displays individual subjects’ height measurements for the ITT population at 4 time points: baseline and endpoint of the Toddler study and baseline and endpoint of the Extension. This figure demonstrates early normalization of height for girls in the ET group by the end of the Toddler study around age 4 years, with almost all height values being above the 5th percentile of the normal curve (and well above the TS reference range [31]), compared with very few values for the EUT group. However, many EUT subjects caught up a few years later, after starting GH during the Inter-study period, and most EUT group height values were above the 5th percentile by Extension study entry around age 8. For the cohort as a whole, more than two-thirds of heights were well within the general population normal range from mid-childhood (around age 7–8 years) onward. Last available height was within the normal range (above −2.0 SDS) for 76% of ET subjects and 60% of EUT (68% overall). Furthermore, 90% of subjects had last height above the mean for untreated adult women with TS (∼144 cm [17]).

Fig. 5.

Individual subject heights at Toddler study baseline and endpoint and Extension study baseline and endpoint (ITT population). Solid lines depict the 5th, 50th, and 95th percentiles of the US Centers for Disease Control growth chart for girls [30]; shaded area represents the mean ±1 SD for Turner syndrome according to the Ranke standard [31]. Heights are shown for individual subjects at Toddler study baseline and endpoint (open and filled circles, respectively) and Extension study baseline and endpoint (open and filled squares, respectively) for the ET group (left graph, blue symbols) and for the EUT group (right graph, red symbols). Note that some early departures mean that endpoint was not at NAH for all subjects. Red “x” symbols represent the subject in the EUT group who was tall at baseline and received no GH at any time. ITT, intent-to-treat; ET, early-treated; EUT, early-untreated; NAH, near-adult height; GH, growth hormone.

Fig. 5.

Individual subject heights at Toddler study baseline and endpoint and Extension study baseline and endpoint (ITT population). Solid lines depict the 5th, 50th, and 95th percentiles of the US Centers for Disease Control growth chart for girls [30]; shaded area represents the mean ±1 SD for Turner syndrome according to the Ranke standard [31]. Heights are shown for individual subjects at Toddler study baseline and endpoint (open and filled circles, respectively) and Extension study baseline and endpoint (open and filled squares, respectively) for the ET group (left graph, blue symbols) and for the EUT group (right graph, red symbols). Note that some early departures mean that endpoint was not at NAH for all subjects. Red “x” symbols represent the subject in the EUT group who was tall at baseline and received no GH at any time. ITT, intent-to-treat; ET, early-treated; EUT, early-untreated; NAH, near-adult height; GH, growth hormone.

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Pubertal Development and Its Associations with Height Outcomes

An important question raised by this study was whether girls who received GH from the toddler years would attain taller heights in the early teen years than girls treated later, allowing for onset of puberty at more physiological ages than in previous studies. As anticipated, at the onset of puberty (Tanner stage ≥B2), the ET group was significantly taller than the EUT group (ET, −1.0 ± 1.4 SDS; EUT, −1.8 ± 1.2 SDS; p = 0.016) and about 6 months younger (12.3 vs. 12.8 years; Table 4). Thus, the Kaplan-Meier curve for onset of breast development is shifted to the left for the ET group compared with the EUT group, particularly after ∼11.5 years of age (Fig. 3b). It should be noted that Tanner breast stage 2 was not observed for some girls, in which case Tanner stage 3 was used as the proxy for pubertal onset, resulting in greater estimates of mean age overall.

Table 4.

Pubertal parameters: ITT population

 Pubertal parameters: ITT population
 Pubertal parameters: ITT population

Of 60 girls for whom pubertal data were available, breast development occurred spontaneously for 19 (32%); not surprisingly, 74% of this subgroup had karyotypes other than 45,X (e.g., 45,X/46,XX; 45,X/47,XXX; 45,X/46,X,r[X]) compared with 31% non-monosomy karyotypes for the study population as a whole (ET, 12/35 [34%]; EUT, 9/32 [28%]). On average, breast development began >2.5 years later for girls whose puberty was induced compared with those who had spontaneous development; 7 of the 19 girls who had spontaneous pubertal onset received estrogen supplementation 1.3–5.6 years later. Menarche occurred on average about 2 years after the onset of breast development (Table 4).

Notably, the ET/spontaneous puberty subgroup attained the best height outcomes overall: mean height SDS at ≥B2 was −0.01 SDS (i.e., equivalent to 50th percentile for non-TS girls), and of the total 19 girls with spontaneous puberty, the ET subgroup was significantly taller (by more than 1.0 SD) at puberty onset than the EUT subgroup (p = 0.03; Table 4). For both ET and EUT, those who had spontaneous puberty were substantially taller for age at pubertal onset than girls whose puberty was induced (height SDS, combined ET/EUT groups: spontaneous, –0.56 vs. induced, –1.83; Table 4). At study endpoint mean height for the ET/spontaneous subgroup was 156.3 cm (∼21st percentile for mean age, 14.7 years) versus 151.7 cm for the EUT/spontaneous subgroup (∼5th percentile for mean age, 15.6 years). The shortest and oldest subgroup at study endpoint was the EUT/induced puberty group, with mean height 150.3 cm (~3rd percentile for age 16.3 years). In general, bone age was slightly ahead of chronological age for the ET group until approximately 11 years of age, whereas it was slightly behind chronological age for the EUT group; thereafter, the curves were almost superimposed (Fig. 6a).

Fig. 6.

a Bone age versus chronological age (mean) by treatment group. ET group, solid blue line; EUT group, dashed red line. Numbers above the X axis are numbers of subjects with bone age X-rays available at each integer age. b Quantitative insulin sensitivity check index (QUICKI) values (mean ± SD) by age and treatment group, with mean years of GH treatment shown above the X axis at each integer age: ET group, solid blue line; EUT group, dashed red line. Horizontal dotted lines represent the mean and SD of QUICKI in healthy prepubertal children [34]. c IGF-I values by treatment group (safety population), plotted against the mean ±2 SD for a cohort of Danish girls [32]. Over the duration of the combined study periods, there were 380 values for the ET group (n = 36; blue circles) and 369 values for the EUT group (n = 33; red crosses). d IGFBP-3 values by treatment group (safety population), plotted against the mean ±2 SD of the range for Danish girls [33]. Over the duration of the combined study periods, there were 380 values for the ET group (n = 36) and 370 values for the EUT group (n = 33). ET, early-treated; EUT, early-untreated; GH, growth hormone.

Fig. 6.

a Bone age versus chronological age (mean) by treatment group. ET group, solid blue line; EUT group, dashed red line. Numbers above the X axis are numbers of subjects with bone age X-rays available at each integer age. b Quantitative insulin sensitivity check index (QUICKI) values (mean ± SD) by age and treatment group, with mean years of GH treatment shown above the X axis at each integer age: ET group, solid blue line; EUT group, dashed red line. Horizontal dotted lines represent the mean and SD of QUICKI in healthy prepubertal children [34]. c IGF-I values by treatment group (safety population), plotted against the mean ±2 SD for a cohort of Danish girls [32]. Over the duration of the combined study periods, there were 380 values for the ET group (n = 36; blue circles) and 369 values for the EUT group (n = 33; red crosses). d IGFBP-3 values by treatment group (safety population), plotted against the mean ±2 SD of the range for Danish girls [33]. Over the duration of the combined study periods, there were 380 values for the ET group (n = 36) and 370 values for the EUT group (n = 33). ET, early-treated; EUT, early-untreated; GH, growth hormone.

Close modal

IGF-I and IGFBP-3

During the Toddler study, IGF-I values were >2 SD above the reference population mean [32] at least once for 29% of the ET group, whereas for the EUT group (i.e., non-GH-treated at that time), all values except 1 were within the normal range, and most were below the population mean (Fig. 6c, up to age 6 years). During the Extension, when almost all girls were receiving GH, a small subset of IGF-I and IGFBP-3 [33] values for both groups was >2 SD above the reference population mean (Fig. 6c, d).

Safety

Glucose Homeostasis

Fasting blood glucose values were elevated (>5.6 mmol/L) for 8/67 subjects (12%) at Extension baseline and for 9% to 21% subjects at various post-baseline visits. However, most of the girls with an elevated value had normal values at their other visits. Two-hour OGTT glucose values were mildly elevated (8.4–9.2 mmol/L; impaired glucose tolerance was defined as ≥7.8 mmol/L to <11.1 mmol/L) in 5 girls (of 148 OGTTs performed during the study overall). Insulin sensitivity was normal (values ≥0.30 on QUICKI [34]; Fig. 6b) at baseline and year 1 of the Extension for all but 1 subject; thereafter, values were subnormal for between 3 and 7 subjects at each annual visit up to year 8 and at the endpoint visit.

One girl was hyperglycemic at Extension study baseline, with an abnormal OGTT and HbA1c 6.1%; type 1 DM was diagnosed 15 months later. There were no other reports of DM (either type 1 or type 2) during the Extension. However, metformin treatment was reported for 3 girls who had evidence of insulin resistance or mildly impaired glucose tolerance. Lipid results were unremarkable.

Adverse Events

Thirteen SAEs were reported for 11/69 subjects (1 subject had 3 SAEs reported): 2 events of neoplasia, described below (2 additional neoplasia-related events were not reported as SAEs, described below); 2 surgeries for scoliosis and 3 for congenital anomalies (atrial septal defect, anomalous pulmonary venous connection, and pterygium colli), 4 hospitalizations for infectious illnesses (cellulitis, gastroenteritis, and pneumonia [2 events]), 1 hospitalization for headache and 1 hospitalization for gastrointestinal hemorrhage.

Four events of neoplasia (2 in 1 subject) were reported in 3 subjects in the ET group during the Extension study. A 10.5-year-old girl presented with a medulloblastoma (reported as SAE), having received ∼11 months of GH treatment from age 1.0 to 2.1 years. The medulloblastoma was treated with surgery, chemotherapy, and cranial irradiation. However, about 2.5 years later, she developed acute myeloblastic leukemia (not reported as SAE), was treated with chemotherapy, and died of complications at age ~13 years. The third neoplastic event was a primary mediastinal stage 1 ganglioneuroblastoma in a 6.6-year-old girl (reported as SAE). The child had received GH from age ∼1.5 to 2.2 years, discontinuing GH when she moved out of state. The tumor was diagnosed incidentally on spinal X-rays performed at 6 years of age for scoliosis screening at Extension study entry. After surgical removal of the tumor, GH was restarted ∼6 weeks later. The fourth neoplasia was a tubulovillous adenoma of the colon (not reported as SAE) in an 11.7-year-old girl who was later found to have a family history of polyposis coli. Apart from a brief suspension of treatment for removal of the adenoma, the child received GH consistently from age 1.6 to 15.7 years.

Based on “Yes/No” checkbox responses on CRFs for prespecified clinically relevant events, there were no reports of pancreatitis, slipped capital femoral epiphysis, or benign intracranial hypertension. However, the following events were reported for at least 1 subject during the Extension: otitis media (n = 21 subjects), scoliosis (n = 21; details below), hypothyroidism (n = 11), mild dilatation of the aorta (n = 4; details below), type 1 DM (n = 1; details below), and hypertension (n = 1). In addition to the prespecified events, treatment-emergent adverse events were reported for 96% of study subjects; most events were typical childhood illnesses (e.g., infections [78%], gastrointestinal disorders [52%], musculoskeletal disorders [48%], and respiratory disorders [41%]), or conditions associated with TS (e.g., procedures for orthodontic problems [16%], ear tube insertion [13%], and tympanoplasty [12%]), all considered unlikely to be GH-related. Mild scoliosis was reported in 21/69 (30%) girls; progression resulted in surgical intervention for 2. Four girls were diagnosed with aortic dilatation, using local institutional criteria, at ages 4.9–15.9 years (GH treatment durations, 2.6–10.8 years). One girl with aortic dilatation also had a bicuspid aortic valve; aortic dilatation was reported to resolve in 1 subject.

In 1999, lacking data on early GH treatment in TS, we initiated the Toddler Turner RCT based on the hypothesis that GH treatment in the preschool years could prevent the progressive growth failure that typically begins in infancy in girls with TS [7, 27]. As detailed in the initial report from that study, our hypothesis was proven correct in the short term [27]. However, the question remained whether the early gains would be maintained throughout the growth period to adult height.

Long-term follow-up of this unique cohort demonstrated different treatment and growth patterns for the earlier-treated (ET) and later-treated (EUT) groups. Lapses in treatment for many ET girls following their 2 years of protocol-specified GH in the Toddler study, and overall similarity of treatment duration between the groups, resulted in a non-significantly greater height SDS for the ET group at NAH. The ET girls caught up to population-normal heights by age 4, but height SDS declined for many girls during untreated periods after the end of the Toddler RCT. Most regained some of the losses after restarting treatment in the Extension phase, such that they were taller at onset of puberty (which began at more physiological ages [35]) than the EUT girls, and mature height was within the normal range for 76%. In contrast, the EUT group showed continued loss of height SDS during their period as untreated controls in the Toddler study, and although the EUT girls grew well after GH initiation in the Interstudy period, substantially narrowing the gap between the groups, they never fully caught up to the ET group, which remained taller by at least 0.4 SDS throughout childhood and adolescence, to maturity. Height was within the lower-normal range for most EUT girls by age 8, but on average they were older and shorter at the start of puberty than the ET girls and fewer attained mature heights within the normal range (60%, vs. 76% for ET). In summary, both growth and maturation occurred earlier (closer to physiological timing) for the ET compared with the EUT group, and mature height was within the normal height range for a greater proportion of ET girls although mean NAH SDS difference did not achieve significance.

Our study provides 3 key observations: first, early GH initiation in girls with TS prevents ongoing growth failure (loss of height SDS) thereby preserving height potential; second, interruption of GH treatment can undermine its efficacy; and third, GH treatment by age 6 should allow attainment of normal adult height for the great majority of patients. Putting these findings together, we conclude that early initiation of GH treatment leads to normalization of height during childhood and favorable height at pubertal age, thus allowing timely estrogen replacement if needed and promoting optimal adult height outcomes.

In our cohort the strongest predictor of NAH SDS was height SDS at GH start. In other words, the taller (and generally, younger) the girl is at baseline relative to population standards, the taller she is likely to be after GH treatment. Because approximately half of the height deficit of girls with TS has already occurred by age 3 [36] and height SDS continues to decline with increasing age in untreated girls [7], the earlier treatment is initiated, the briefer will be the duration of growth failure and therefore the smaller the loss of height potential. Translating our finding to individualized patient care indicates that early treatment is likely to be especially relevant in girls who are already short at a young age, because if untreated these girls are most likely to attain short adult heights that are physically and/or socially problematic. The strong association between baseline height SDS and adult height SDS, coupled with the fact that prepubertal growth has the greatest impact on overall height gain [37, 38], supports the approach of initiating GH soon after diagnosis of TS to prevent the growth failure that otherwise occurs with advancing age.

In addition to favorable growth outcomes for both the ET and EUT groups, our study provides reassurance regarding long-term GH safety in TS. Most reported adverse events were typical childhood illnesses unrelated to GH, or conditions associated with TS irrespective of treatment. However, certain events warrant discussion. Two neoplastic conditions (medulloblastoma and ganglioneuroblastoma) were of neural origin, and previous data (including case reports as early as the 1960s, before the use of GH in TS) have suggested a predisposition to development of ganglioneuroma, neuroblastoma, and related tumors in girls with TS [39‒42]. The third de novo neoplasm in our study was a colon adenoma in a girl with a family history of adenomatous polyposis, an autosomal dominant condition that predisposes to colon adenoma and cancer [43]. Notably, Danish GH registry data demonstrated a 5- to 7-fold greater relative risk of colon cancer in women with TS versus general population rates, whereas overall TS cancer rates were not elevated [44, 45]. Furthermore, a large pediatric post-marketing study found no increase in cancer rates in patients with TS versus other GH-treated patient groups [46]. The events observed in our study therefore appear to fall within the spectrum of neoplasia previously reported in TS, irrespective of GH exposure, and did not occur unusually early. Nevertheless, physicians should advise families that the prescribing information for recombinant GH contains a warning regarding an increased risk of second neoplasm in childhood cancer survivors treated with cranial irradiation who later receive GH treatment.

Aortic dilatation, a serious concern for women with TS, was reported in 4 girls in our study. However, false positives for children were reported commonly during the 2000s due to failure to index aortic dimensions to body surface area and absence of TS-specific standards [47]; available data suggest no GH-related increase in risk of this disorder [48].

Although both treatment groups had positive outcomes overall, with mature height in the normal range for 76% of the ET group and 60% of the EUT group, our study had certain limitations. First, the long-term follow-up component of this study was not part of the original design, but was added after the Toddler study had completed resulting in some inconsistencies of treatment after the 2-year controlled period. Most girls transitioned smoothly onto GH treatment after the Toddler study, continuing through the Inter-study period to the Extension study, however, 40% of the ET group had a treatment gap of at least 1 year after their 2 years of GH in the Toddler phase. Girls whose GH treatment was interrupted showed considerable catch-down growth while off GH, in some cases reversing the gains made during the Toddler study. This loss of height SDS in the ET group during the Inter-study period was a key factor reducing the between-group difference at NAH. Although the inconsistency of treatment may be viewed as a deficiency, this finding also reflects the real-world experience of some patients in clinical practice, whose treatment may be interrupted for medical, social, or financial reasons. Whatever its basis, the detrimental impact of treatment interruption on overall outcome provides a lesson on the importance of maintaining consistent GH treatment where possible until a satisfactory mature height has been attained, thereby avoiding the phenomenon referred to by Tanner 50 years ago as “regulatory deceleration” [49].

In addition to the impact of lapses in GH treatment for ET subjects after the Toddler study, the second factor reducing the long-term between-group difference was the fact that the cumulative GH exposure of our groups was, in the end, more similar than it was different. Because the ET girls started GH about 2–3 years earlier they also finished about 1.5 years earlier than the EUT group, so by the time they attained NAH both groups had similar GH treatment duration of >10 years (including more than 7 years before puberty, the time of greatest effectiveness). Thus, with only a few months’ difference in overall GH duration, it is not surprising that height SDS difference was not significant at maturity.

The third issue that may have affected our results was the lack of NAH data for 24% of the Extension cohort overall, reflecting the challenges of following young children for 10–15 years, as was also observed in the only placebo-controlled RCT to adult height in TS [50]. Nevertheless, among our 16 study subjects who did not have NAH available (of 66 GH-treated subjects in the combined-group ITT population), 10 were at least 14.5 years old at last visit, with average height 151.6 cm – very similar to that of the NAH analysis population – supporting the robustness of the efficacy data.

Despite some limitations, these results support our approach to clinical management of growth failure in girls with TS. Our study began with a paradigm different from traditional GH treatment approaches: rather than aiming to repair height deficits acquired over a period of progressive growth failure, we aimed to prevent loss of height potential (relative to non-TS peers) before it occurs. Consequently, the key measure of efficacy is attainedor actual height SDS at a given time, rather than changein height SDS from baseline (a typical efficacy measure in earlier studies), which is minimized by preventing loss of height SDS with early treatment. The fact that average height SDS of our ET group was within 1.5 SDS of the general population mean for age from early childhood to maturity provides evidence of the success of our strategy in preventing growth failure and maintaining normal height for most girls.

Our study is one of only 5 published TS studies that followed a nontreatment parallel group for at least 1 year [51]. Of these 5 studies, only 2 can be considered “gold-standard” studies, having followed untreated (or placebo) controls to adult height to provide the most robust assessment of long-term GH treatment effect. The average AH/NAH values for the GH-treated groups in those studies (starting at mean ages ~9–10 years) were 147.5–147.9 cm, compared with mean last available height of 152.3 cm in our NAH population (ET/EUT groups combined) [14, 50]. Furthermore, 76% of our ET NAH group had height within the general population reference range (above −2.0 SDS) at last measurement, versus 40–50% of GH-treated subjects in the earlier studies and only 4–5% of non-GH-treated control subjects in those studies. Importantly, earlier initiation of treatment in our study allowed taller height at pubertal age and more physiological timing of puberty than in the earlier studies.

As we hypothesized over 20 years ago, early initiation of GH can prevent TS-related growth failure [27]. However, whenever possible treatment should be maintained consistently until a satisfactory final height is attained, otherwise the efficacy may be undermined by catch-down growth after treatment discontinuation. Our approach of preventing ongoing growth failure and preserving the child’s genetic height potential by early initiation of GH treatment is paralleled by the changes in published TS treatment guidelines over the past quarter-century [25, 51‒53], which have moved progressively away from withholding GH until the patient’s height “has dropped below the 5th percentile of the normal female growth curve” [52]. We concur with the current guidelines’ assertion that “younger age at [GH] treatment initiation, including at least 4 years of treatment prior to puberty [should] allow for age-appropriate induction of feminization, such that the goals for both optimal adult stature and timing of puberty can be achieved” [51]. However, we do not believe it is in the child’s best interest to wait until she “already has evidence of growth failure (e.g., below 50th percentile height velocity…), [or] “is already short” The height deficits at school entry in untreated girls are large (average ∼9–11 cm by age 4–6 years [7]) and difficult to repair, potentially compounding the significant medical, psychosocial, and educational challenges faced by many girls with TS. Prevention of such deficits is an achievable goal.

In summary, our 10-year extension to the Toddler Turner RCT provided positive outcomes for both treatment groups but, largely because of lapses in treatment for the ET group after the initial 2 years, we did not demonstrate a significant impact on NAH of starting GH by 4 years of age versus starting ~2 years later. Nevertheless, taller height for age at GH initiation (therefore, generally younger age), before substantial loss of height potential has occurred, results in the best long-term height outcomes. Based on our findings, we conclude that starting GH treatment before the age of ∼6 years is effective in preventing growth failure, maintaining growth potential and offering the advantages of normal height at key developmental time points such as school entry and onset of puberty. Early initiation of GH followed by uninterrupted treatment during childhood will provide the foundation for optimal adult height outcomes.

The authors thank the subjects and their families for their participation in this study, and Nan Jia, Anthony J. Zagar, and Brenda J. Crowe for statistical design and consultation. Our study would not have been possible without the unfailing support of the dedicated nurses and clinical coordinators at the study centres.

The study protocol (Clinical Trial Registry No. NCT00266656) was approved by the Ethics Review Boards of the participating institutions and conducted according to the standards of the World Medical Association Declaration of Helsinki. Written informed consent for all study-specific procedures was obtained from the subjects’ parents or legal guardians and assent was obtained from participants according to the institutional guidelines.

C.A.Q., E.A.E., R.L.H., F.U., K.R., S.T., and M.L.D. declare no conflicts of interest. P.Y.F. has a research contract from Pfizer. M.E.G. has a research contract from Novo Nordisk; is an advisory board member of Adrenas, Daiichi Sankyo, Ferring, Neurocrine Biosciences, Novo Nordisk, Nutritional Growth Solutions, Pfizer, QED, and Spruce Biosciences; is a member of data safety monitoring boards for Ascendis, Millendo, and Tolmar; and receives royalties from McGraw-Hill and UpToDate. J.L.R. is an advisory board member of Novo Nordisk and OPKO. C.J.A. and H.P. are employees and shareholders of Eli Lilly and Company.

The study was funded by Eli Lilly and Company, Indianapolis, IN, USA. Lilly was responsible for data collection, storage and analysis, and for review and approval of the manuscript. In compliance with the Uniform Requirements for Manuscripts established by the International Committee of Medical Journal Editors, the sponsor of this study did not impose any impediment, directly or indirectly, on the publication of the study’s results.

C.A.Q. and M.L.D. conceived and designed the study. Anthony J. Zagar designed the primary statistical analyses in partnership with C.A.Q. and M.L.D. C.A.Q. and M.L.D. interpreted the data and drafted the manuscript. All authors acquired the data and provided critical review and approval of the manuscript.

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