Letrozole Monotherapy in Pre- and Early-Pubertal Boys Does Not Increase Adult Height

Abstract

Background: Aromatase inhibitors (AIs) have been used in boys with idiopathic short stature (ISS) to promote growth despite the lack of actual data regarding treatment effect on adult height. In this study, we characterized adult heights and long-term follow-up in AI-treated boys with ISS. Methods: Adult heights and long-term follow-up data, including spine MRIs, of a randomized, double-blind, placebo-controlled trial of boys who were treated with letrozole (Lz) (2.5 mg/d) or placebo (Pl) for 2 years during prepuberty and early puberty. The mean bone ages at treatment cessation were 10.2 and 10.8 years, respectively. Results: Adult heights were similar between the boys treated with Lz ( n = 10) and those who received Pl ( n = 10) (164.8 ± 4.0 vs. 163.7 ± 3.7 cm, p = 0.49, respectively). In either group, the adult heights did not differ from predicted adult heights at start of the study [Pl: 163.7 (3.7) cm vs. 166.9 (3.3), p = 0.06; Lz: 164.8 (4.0) cm vs. 167.6 (7.9), p = 0.20, respectively]. Long-term follow-up data showed that the frequency of subjects with a vertebral deformity was similar between the groups (Lz, 29% and Pl, 22%, p = 0.20), and no single comorbidity was clearly enriched in either group. Conclusions: The Lz-treated boys had similar adult heights with the subjects who received Pl for 2 years, which indicates that the treatment is not beneficial when given to pre- or early-pubertal boys. Previously observed vertebral deformities ameliorated during follow-up, which supports the skeletal safety of Lz therapy in children and adolescents.

Treatment of Short Stature with Aromatase Inhibitors: A Systematic Review and Meta-Analysis

“…Safety is a potential concern regarding AI therapy. Our results are not consistent with those of previous studies [18]. Hero et al [17] reported that 5 of 11 patients (45 %) treated with AI had vertebral deformities; however, no patient had a vertebral deformity in the group treated with a placebo.…”

“…Fourteen studies that matched the inclusion criteria included 388 male patients with ISS [12,16,18,20,21], CDGP [11,17,[22][23][24][25][26], GHD [10], and ICPP [14], 193 patients with AI use, and 195 controls. Two studies described boys with ISS treated with AI plus rhGH and rhGH alone [16,21], five compared AI plus T with T [11,17,22,24,26], and the other studies investigated AI and placebos [10,12,14,17,18,20,23,25]. Among the studies, Hero et al [17] included two different intervention cohorts: the first cohort included males with ISS treated with letrozole or placebo, and the second cohort includ-▶table 1 Brief characteristics of included random controlled trials.…”

“…Moreover, vertebral anomalies were observed at follow-up in boys who received letrozole before the onset of puberty, but not in a theletrozole-treated group of older boys with CDGP. Nevertheless, a long-term follow up study showed that such vertebral deformities had normalized in two of three patients [18]. It was postulated that this may have been because the patients were older, had a more advanced bone age, and received treatment for a shorter duration.…”

“…AIs have also been combined with testosterone (T) in children with CDGP [17]. However, not all studies have found that AIs increases growth potential in patients with ISS [18,19]. For example, McGrath et al observed that some adverse events are associated with an increase in final height (FH) [15].…”

Should Skeletal Maturation Be Manipulated for Extra Height Gain?

“…At discontinuation of medication there was a 5.9 cm increase of PAH on letrozole ( 123 ), but the authors have to be praised for performing a study on attained AH. This showed that there was no statistically significant difference in AH ( 124 ) (LoE 1). Of note, in both groups, the attained AH was 3 cm lower than PAH at start of treatment ( 124 ).…”