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Absence of Growth Hormone Effects on Cognitive Function in Girls with Turner Syndrome ¹

Department of Pediatrics (J.L.R.), Thomas Jefferson University; Hahnemann University (H.K.), Philadelphia, Pennsylvania 19107; Department of Neurology (D.R.), Williamsport Hospital, Williamsport, Pennsylvania 17701; The Developmental Endocrinology Branch (P.F., G.B.C.), NICHD, NIH, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Judith L. Ross, M.D., Thomas Jefferson University, Department of Pediatrics, 1025 Walnut Street, Philadelphia, Pennsylvania 19107.

	Abstract

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Turner syndrome (TS) is a genetic disorder characterized by short stature, gonadal dysgenesis, and a particular neurocognitive profile of normally developed language abilities (particularly verbal IQ) and impaired visual-spatial and/or visual-perceptual abilities. We have followed a large sample of girls with Turner syndrome who were enrolled in a long-term, double-blind, placebo-controlled trial of the effects of growth hormone (GH) treatment on final adult height. This study provides a unique opportunity to prospectively evaluate the effects of GH treatment on neurocognitive function in this population of girls with Turner syndrome. The GH- and placebo-treated Turner syndrome subjects were well matched for age, treatment duration, race, karyotype, and socioeconomic status. Treatment (GH or placebo) durations ranged from 1–7 yr. Whether GH deficiency and/or treatment in childhood and adolescence influences cognitive outcome in short children or GH-children is controversial. The major result of this study was the absence of GH treatment effects on cognitive function in girls with Turner syndrome. Our findings are in agreement with most of the previous studies that found no apparent growth hormone treatment effects on cognitive function in growth-hormone deficient children. We conclude that this study does not support a role for growth hormone in influencing childhood brain development in girls with Turner syndrome. Their characteristic nonverbal neurocognitive deficits were not altered with GH treatment into early adolescence.

	Introduction

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MOST STUDIES indicate that cognitive function in children with short stature and growth hormone (GH) deficiency is normal (1, 2, 3). Meyer-Bahlburg, et al. (3) studied 29 children with idiopathic GH deficiency and reported normal full scale intelligence quotient (IQ) distributions and absence of deficits in specific cognitive domains in the group. IQ was not significantly correlated with age at onset or length of GH treatment, and there was no difference between patients treated vs. those not treated with GH (3). Other studies have shown cognitive deficits in children with GH deficiency secondary to hypopituitarism and/or GH treatment effects on cognitive function of GH-deficient children (4, 5, 6). Siegal and Hopwood (4) found a difference between verbal and performance subtests in hypopituitary children that was greater than expected. Smith et al. (5) showed enhanced performance on attention tasks in children who received GH injections in a double-blind placebo-controlled trial. Other investigators noted improved memory in adults with multiple GH deficiencies who had received GH treatment (6). In summary, whether GH deficiency and/or treatment in childhood and adolescence influences cognitive outcome in short children or GH-deficient children is controversial.

Turner syndrome (TS) is a genetic disorder occurring in 1 in every 2,500 female births and is characterized by short stature, gonadal dysgenesis, and a particular neurocognitive profile of normally developed language abilities (particularly verbal IQ) and impaired visual-spatial and/or visual-perceptual abilities (7, 8, 9, 10, 11). The most frequently described profile in TS includes difficulty with tasks involving memory and attention, decreased arithmetic skills, and impaired visual-spatial processing (9). We have followed a large sample of girls with Turner syndrome who were enrolled in a long-term, double-blind, placebo-controlled trial of the effects of GH treatment on final adult height. The children were randomly assigned to a GH or placebo group. This study provides a unique opportunity to evaluate prospectively the effects of GH treatment on neurocognitive function in this population of girls with Turner syndrome. We also investigated whether age at onset of GH treatment would influence the neurocognitive outcome by studying younger (7–9 yr old) and older (10–12 yr old) TS girls with a specifically constructed neurocognitive battery of tests designed to focus on neurocognitive deficits previously described.

	Subjects and Methods

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Subjects

This study was approved by the Human Studies Committee of the National Institute of Child Health and Human Development at the National Institutes of Health and at Thomas Jefferson University. Informed consent and assent was obtained in all cases. Socioeconomic status (SES) was calculated on each subject according to the method of Hollingshead (12).

The TS girls who participated in the study were drawn from an on-going placebo-controlled double-blind study of the effects of GH on final adult height. They were eligible to start the study between the ages of 5 and 11.9 yr, and they came from all parts of the United States. The diagnosis of Turner syndrome was confirmed by karyotyping. Estrogen-treated girls were excluded from this analysis because of potential estrogen effects on cognition. In addition, no subjects had received any earlier treatment with androgens. The GH (Humatrope) was given in the dose of 0.1 mg/kg/dose, three times weekly (sc injection) and was kindly supplied by Eli Lilly and Company (Indianapolis, IN). The evaluation took place approximately 36 h after the preceding dose of GH or placebo. Treatment (GH or placebo) durations ranged from 1–7 yr, depending on the age of the child at entry into the growth study and at the time of the cognitive evaluation. No children with a verbal IQ of less than 70 were included because these children are likely to have more diffuse developmental delay rather than the typical TS neurocognitive profile.

All testing was conducted at Thomas Jefferson University Hospital and the National Institutes of Health by trained psychometricians. The specific tests employed to examine each neurocognitive domain are described in Table 1.

Two-way analysis of variance (ANOVA) was used for comparisons between GH and placebo-treated TS subjects in two age ranges: 7.0–9.9 yr and 10.0–12.9 yr. Chi-squared analysis was performed for the comparison of race and karyotype in the two groups. All statistical tests are two-tailed tests, and the results are presented as mean ± standard deviation ([sd]). P values for all comparisons are listed and are presented without adjustment for multiple comparisons. Corrections for simultaneous multiple comparisons can be performed using Bonferroni type adjustments. On that basis, only P values less than 0.001 would be considered statistically significant.

	Results

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The GH- and placebo-treated TS subjects were well matched for age, duration of treatment, race, karyotype, and SES (Table 2).

	Discussion

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According to our results, GH treatment durations of 1–7 yr did not appear to influence any of the cognitive outcome variables. Our groups were well matched for socioeconomic status, which eliminated the potential influence of SES on differences in outcome variables. Previous studies of the relationship between height and cognitive outcome in normal boys indicate that SES accounts for much of the correlation between physical size and cognitive results. When SES and head circumference were controlled, the observed correlations diminished in significance (13).

Our findings are in agreement with most of the previous studies that found no apparent GH-treatment effects on cognitive function in GH-deficient children (1, 3). The previous studies of positive GH effects included a different population of children or adults who were GH deficient (5, 14). Girls with TS are generally not classically GH-deficient, particularly in the early childhood years (15). Therefore, GH treatment in the age range of this study (5–12 yr) would not be expected to correct any underlying deficiency.

A study of adult men with GH deficiency found impaired memory in men with isolated GH deficiency and impaired perceptual-motor skills and memory scores in men with multiple pituitary hormone deficiencies (14). The latter group of males were also deficient in testosterone, thyroid hormone, and/or ACTH. Deficiencies in all these other hormones could also have a negative impact on brain development before and after birth. In addition, children born with multiple pituitary deficiencies were more likely to have had a life-threatening event in the newborn interval or during childhood, secondary to hypoglycemia related to GH- or ACTH-deficiency, or secondary to symptoms of adrenal insufficiency. Finally, the GH-deficient group may have been deficient even during fetal development. GH may influence brain development before birth. The TS population differs from these groups in that they are not classically GH deficient in early childhood, and they do not have multiple pituitary deficiencies. However, they do have gonadal dysgenesis and absence of ovarian estrogen production, which may affect brain and cognitive development.

We conclude that this study does not support a role for GH in influencing the characteristic nonverbal neurocognitive deficits associated with TS. In addition, these results provide no evidence supporting GH effects on brain development of girls with TS treated into early adolescence. The potential treatment effects of other hormones, including estrogen and androgen, on the TS neurocognitive profile are currently under investigation by our group.

	Footnotes

 
¹ This work was supported in part by NIH Grant NS29857 and by Eli Lilly and Company.

Received December 5, 1996.

Revised February 20, 1997.

Accepted March 5, 1997.

	References

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