ESPE Yearbook of Paediatric Endocrinology

Clinical Endocrinology. 2022; 96:220–226. PMID: 34596269

Brief Summary: This randomized controlled trial evaluated the effects of testosterone and aromatase inhibitor treatment on anthropometric measures, and their correlation with estradiol and testosterone serum levels in boys with constitutional delay of growth and puberty (CDGP), to elucidate the respective roles of the two sex steroid hormones on growth during puberty. The results suggest that testosterone plays a major role in pubertal growth, being the best predictor of growth velocity, although adjuvant action of estrogens appears necessary to optimize growth. Extended trials should be warranted to draw clinical indications on the use of testosterone and aromatase inhibitors in CGDP.

During puberty, the gonadotropic axis plays a pivotal role in linear growth, interacting synergistically with somatotropic axis. Indeed, sex steroids, both androgens and estrogens, induce pubertal growth spurt. Sex steroids stimulate the growth hormone (GH)/insulin growth factor-1 (IGF-1) axis but have also a direct effect on bone and cartilage growth plate (1). The respective importance of testosterone and estrogens in the regulation of pubertal growth acceleration is unclear. Constitutional delay of growth and puberty (CDGP) is a variant of the normal process of growth and represents the most frequent cause of delayed puberty in males. It is typically characterized by normal growth during childhood, prepubertal deceleration of height velocity (HV), delayed bone age (BA) and absence of secondary sexual characteristics. In boys, treatment with testosterone increases serum testosterone, estradiol and IGF-1 concentrations, whereas aromatase inhibitors increase serum testosterone only.

In this randomized controlled trial, 28 boys with CDGP (mean age 14.7 ± 0.58 years, mean bone age 12.4 ± 1.1 years, mean testicular volume 3.1 ± 0.92 ml, mean serum testosterone 2.1 ± 1.2 nmol/L) were treated for 6 months with either low-dose intramuscular testosterone (T; n=14; 1 mg/kg/month) or the aromatase inhibitor letrozole (Lz; n=14; 2.5 mg/day). Anthropometry and serum concentrations of testosterone, estradiol and IGF-1 were assessed at 0, 3 and 6 months. Serum testosterone and estradiol concentrations correlated with growth velocity after 6 months of treatment in both groups, with testosterone being the best predictor of growth velocity for both treatment arms. Each nmol increase in serum testosterone increased growth velocity 2.7 times more in the T group compared to Lz group. Only the boys with serum estradiol > 10 pmol/L had a growth velocity > 8 cm/year.

The authors conclude that testosterone increases growth velocity independently of aromatization to estrogens. However, some level of estrogen is needed to optimize the growth rate during puberty. Serum testosterone one week after the injection and serum testosterone and estradiol three months after the onset of aromatase inhibitor treatment can be used as biomarkers for treatment response. Though these results may have potential clinical impact on the management of children with CDGP, the limited number of participants and the estrogen levels lower than assay sensitivity limits, mitigate the value of the study.

Reference: 1. Veldhuis JD, Roemmich JN, Rogol AD. Gender and sexual maturation-dependent contrasts in the neuroregulation of growth hormone secretion in prepubertal and late adolescent males and females--a general clinical research center-based study. J Clin Endocrinol Metab 2000; 85:2385–2394.