Cognition, Health-Related Quality of Life, and Psychosocial Functioning After GH/GnRHa Treatment in Young Adults Born SGA

Wesley Jim Goedegebuure; Manouk van der Steen; Justine Lenneke de With; Anita Hokken-Koelega


J Clin Endocrinol Metab. 2018;103(11):3931-3938. 

In This Article

Abstract and Introduction


Background: Children born small for gestational age (SGA) with a poor adult height (AH) expectation benefit from treatment with GH and additional gonadotropin-releasing hormone analog (GnRHa). Because both SGA birth and GnRHa treatment might negatively influence cognition, health-related quality of life (HRQoL), and psychosocial functioning, we assessed these outcomes at AH.

Methods: A randomized, dose-response GH study until AH involving 99 adolescents born SGA, of whom 61 children received 2 additional years of GnRHa treatment. At AH, the Wechsler Adult Intelligence Scale and TNO-AZL Adults Quality of Life questionnaire were administered to the study group. Additionally, the study group and 67 adolescents born SGA (19 GnRHa) from a second study group completed the Self-Perception Profile of Adolescents and Child/Adolescent Behavior Checklist at AH. Scores in GH-treated young adults with GnRHa treatment (GH/GnRHa group) were compared with GH-treated adolescents without GnRHa treatment (GH group) and a reference population.

Results: Mean age (SD) at AH was 17.5 (1.2) and 17.4 (1.4) years in the GH/GnRHa and GH group, respectively. Intelligence quotient scores were similar in GH/GnRHa and GH groups (96.33 vs 92.47). HRQoL was similar between both groups and also when compared with the reference population, but the GH/GnRHa group had a significantly lower perception of cognitive functioning. Self-perception and problem behavior were similar in the GH/GnRHa and GH groups. AH did not correlate with HRQoL, self-perception, or problem behavior.

Conclusion: Combined GH/GnRHa treatment has no long-term negative effects on cognition, HRQoL, self-perception, and behavior in early adulthood, compared with GH treatment only.


Being born small for gestational age (SGA) has been associated with problems in health-related quality of life (HRQoL), behavior, and cognitive development.[1–6] In short SGA children without sufficient catch-up growth, long-term continuous recombinant GH treatment leads to an improvement in adult height (AH).[7–9] Additional gonadotropin-releasing hormone analog (GnRHa) treatment of 2 years at the start of puberty increases AH in both boys and girls who start GH treatment at the onset of or in early puberty with an expected AH of <−2.5 standard deviation score (SDS).[10]

GnRH influences structures outside the pituitary region, in the hippocampus and other limbic structures.[11–13] GnRHa treatment may therefore have cognitive effects, as has been shown during 2 years of GnRHa treatment in precocious puberty. Cognitive functioning at cessation of GnRHa treatment tended to be lower in the group receiving 2 years of GnRHa treatment.[14,15] However, it is unknown whether GnRHa treatment affects long-term cognitive functioning.

Short stature has a negative effect on HRQoL, and GH treatment improves HRQoL.[16–19] We have shown that 2 years of GnRHa in addition to GH treatment did not have adverse effects on HRQoL in children born SGA during 2 years of treatment.[20] However, the postponement of puberty might negatively affect problem behavior and school skills later in life.[21] Furthermore, GnRHa treatment has been linked to a suppressed reward system, causing subsequent depressive emotions when used for endometriosis and during fertility treatment. However, these populations differed greatly from children who receive GnRHa treatment of the purpose of postponing puberty.[15,22] Data on the long-term effects of pubertal suppression—by means of 2 years of GnRHa in addition to GH treatment—on HRQoL, self-perception, and problem behavior in early adulthood are lacking.

The primary objective of this study was to assess cognitive functioning and HRQoL after attainment of AH in subjects who participated in Dutch GH trials involving children born SGA treated with GH, either with or without additional 2 years of GnRHa treatment after onset of puberty. In addition, we tested self-perception and problem behavior in these subjects, to evaluate psychosocial functioning at AH.

We hypothesized that postponement of puberty by 2 years of GnRHa treatment in GH-treated young adults born SGA does not negatively influence cognitive functioning, HRQoL, self-perception, or problem behavior in early adulthood compared with GH treatment only. Additionally, we hypothesized that AH would positively correlate with HRQoL and self-perception and negatively with problem behavior and that a double GH dosage of 2 mg/m2/d (~0.067 mg/kg/d) would not influence these outcomes.