Aromatase inhibitors for short stature in male children and adolescents

Review question

This review considered whether a class of medications called aromatase inhibitors could increase adult height in male children and adolescents.

Background

Aromatase inhibitors are an orally available medicine used to prevent conversion of the male hormone, testosterone, to oestrogen. In both sexes, oestrogen causes closure of the growth plates (areas produce new bone growth and so lengthen bones) in long bones (e.g. thigh bone) when growth is complete at the end of puberty. Blocking this conversion in boys reduces oestrogen levels and can prolong the period of growth, and theoretically increase adult height. Oestrogen is important for female pubertal development, and thus, aromatase inhibitors are not suitable for use in teenage girls. Aromatase inhibitors are currently not approved to treat short stature but are rather used as an 'off-label' medicine (i.e. they are licensed to treat other illnesses).

Study characteristics

We searched scientific databases for clinical trials comparing an aromatase inhibitor with placebo or no treatment. We identified four trials (involving 207 male participants) that met inclusion criteria. In one trial, participants received co-treatment with growth hormone (a hormone that causes growth) and, in another trial, participants had six months' co-treatment with testosterone. Underlying diagnoses of study participants included short stature of unknown cause, delayed puberty, or lack of growth hormone. Due to differing study designs, only descriptions of individual trials were available and there were no opportunities for combining the trial results.

Key results

Short-term growth outcomes such as predicted adult height (there is currently no proven way to predict a child's adult height accurately, several formulas are used to provide a reasonable guess for child growth) improved in all trials. However, only one trial reported final adult height data, and demonstrated no relevant difference. There was concern that final adult height data were not published for the other studies. Aromatase inhibitors were generally well tolerated and no participants withdrew from the trials because of side effects. However, only one publication reported detailed information regarding side effects. There were concerns regarding the rate of abnormalities in the spine of 45% of young boys who were treated before entering puberty. None of the trials provided information on overall health-related quality of life or costs.

Quality of the evidence

We considered the overall quality of the evidence of the included trials as low or moderate, mainly because of the small number of trials and participants. There remain concerns regarding non-publication of final height data.

Status of the evidence

This evidence is up to date as of August 2014.

Authors' conclusions: 

Available evidence suggested that aromatase inhibitors improved short-term growth outcomes. There was no evidence to support an increase in final adult height, based on limited data, with only one of four trials publishing final height data under non-randomised conditions.

Read the full abstract...
Background: 

As a result of the essential role of oestrogens in epiphyseal closure, aromatase inhibitors have been trialled as an intervention to improve height outcomes in male children and adolescents by inhibiting the conversion of testosterone to oestradiol.

Objectives: 

To assess the effects of aromatase inhibitors in male children and adolescents with short stature.

Search strategy: 

To identify relevant trials, we searched the Cochrane Library (2014, Issue 7), MEDLINE, EMBASE, and the World Health Organization (WHO) ICTRP trial register from their inception until August 2014. In addition, we conducted citation searches and screened reference lists of included trials.

Selection criteria: 

We included randomised controlled trials (RCTs) if they compared use of an aromatase inhibitor with placebo in male children and adolescents with short stature.

Data collection and analysis: 

Two authors independently screened titles and abstracts for relevance. Both authors carried out screening for inclusion, data extraction, and risk of bias assessment, with any disagreements resolved following discussion. We assessed trials for quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument. We contacted study authors regarding missing information. Primary outcomes were final or near-final height, adverse events, and health-related quality of life. Secondary outcomes included all-cause mortality, cognitive outcomes, socioeconomic effects, laboratory measures, short-term growth parameters, and assessment of effects on bone health. Meta-analysis was not appropriate due to the substantial clinical heterogeneity between trials; we presented the findings of the review in narrative format.

Main results: 

We included four RCTs involving 207 participants (84 on interventions) in the review. Trials included males with constitutional delay of growth and puberty (CDGP), idiopathic short stature (ISS), and growth hormone (GH) deficiency. Three of the trials had an overall low or unclear risk of bias for primary outcomes. Short-term growth outcomes, such as predicted adult height, improved in all trials. Just one trial reported the primary outcome of final and near-final height as an extension under non-randomised conditions. None of the trials assessed health-related quality of life. One publication provided detailed information regarding the incidence of adverse events. A significant proportion (45%) of prepubertal boys with ISS treated with letrozole developed mild morphological abnormalities of their vertebrae, compared with none in the placebo group.

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