Growth Hormone Therapy of Turner Syndrome: The Impact of Age of Estrogen Replacement on Final Height¹

Abstract

Clinical trials of recombinant human GH therapy in Turner syndrome that began more than a decade ago show that GH accelerates the linear growth rate. Several studies indicate that final height is also improved, although the magnitude of the increase has been debated. The age at which feminization is induced could be an important factor in determining the patient's ultimate growth response. To test this, 60 patients from a large (n = 117), previously unreported, clinical trial of GH treatment were randomly assigned to begin conjugated estrogens at either 12 or 15 yr of age. The 60 patients were all less than 11 yr of age at entry (mean, 9.5 yr) and received 0.375 mg/kg x week of GH for nearly 6 yr on a daily or three times weekly regimen. Height gain was calculated by comparing the study patients' final or near final heights to their pretreatment projected heights as well as to those of a separate set of age-matched, historical control patients. Patients in whom estrogen treatment was delayed until age 15 yr gained an average of 8.4 +/- 4.3 cm over their projected height, whereas those starting estrogen at 12 yr gained only 5.1 +/- 3.6 cm, on the average (P < 0.01). Analysis of the interval data showed that growth was stimulated for approximately 2 yr after estrogen initiation, but then declined in association with bone age advancement. Patients who were older than 11 yr at entry (n = 57) all initiated estrogen 1 yr after beginning GH and showed a mean gain in adult height of 4.7 cm, similar to those given estrogen at age 12 yr. Multivariate analysis revealed that the number of years of GH therapy before estrogen treatment was a strong factor in predicting height gained, indicating that the timing of estrogen introduction is an important determinant of final height in this cohort of GH-treated patients with Turner syndrome matched for baseline age and other characteristics.

Effects of hypogonadism on brain development during adolescence in girls with Turner syndrome

“…To increase the final adult height of girls with TS, postponing ER therapy until the mid-teens has been commonly recommended because estrogen/puberty accelerates epiphyseal fusion and thereby reduces adult height (Chernausek, Attie, Cara, Rosenfeld, & Frane, 2000;Saenger et al, 2001;Tanner, Whitehouse, Hughes, & Carter, 1976).…”

Growth Hormone Treatment for Short Stature in the USA, Germany and France: 15 Years of Surveillance in the Genetics and Neuroendocrinology of Short-Stature International Study (GeNeSIS)

“…More than 70% of children born SGA or with SHOX deficiency and 55–70% of girls with Turner syndrome achieved NAH within the normal range. The smaller height gains in patients with Turner syndrome may reflect the wider impact of loss/aberration of an X chromosome and/or bone growth alterations related to skeletal dysplasia and the timing of oestrogen replacement in the presence of ovarian failure [28, 29]. In addition, final height of girls with Turner syndrome is positively influenced by height at GH initiation, the GH dose and age at onset of puberty, and negatively influenced by age at treatment initiation [29, 30].…”

Effect of Oxandrolone and Timing of Oral Ethinylestradiol Initiation on Pubertal Progression, Height Velocity and Bone Maturation in the UK Turner Study

“…Using a similar low-dose of E 2 for pubertal induction, van Pareren et al [16] also reported stabilisation of HV for one year in TS girls who commenced oestrogen at 12 years, but subsequent HV data were not provided. Similarly, Chernausek et al [12] reported that TS girls treated with oral Premarin at 12 or 15 years maintained their HV for one year. Subsequently, a rapid deceleration was observed in girls who commenced oestrogen at 12 years but no further HV data were described for those treated at 15 years.…”

“…However, there was no further analysis of the BA data after one year of E 2 treatment [16]. In a separate study, Chernausek et al [12] reported that when higher oestrogen doses (oral 0.3 mg Premarin/day: conjugated equine oestrogens; ∼5 µg/day EE 2 ) were employed from the outset, a significant increase in bone maturation was noted in girls who commenced oestrogen at 12 versus 15 years during the year that oestrogen was started (mean change in BA/CA: 1.5 vs. 0.9).…”

“…An improved FH outcome with early GH treatment has been shown in some [7,8,9] but not all studies [10,11]. Recent reports suggest that the duration of GH treatment prior to pubertal induction may be predictive of outcome [7,12] and a minimum of 4 oestrogen-free years should be the goal [13]. The optimal age at which to start oestrogen replacement is controversial.…”