Abstract: We included six trials with 498 participants with TS, 267 participants were randomised to oxandrolone plus GH treatment and 231 participants were randomised to GH only treatment. The individual trial sample size ranged between 22 and 133 participants. The included trials were conducted in 65 different paediatric endocrinology healthcare facilities including clinics, centres, hospitals and academia in the USA and Europe. The duration of interventions ranged between 3 and 7.6 years. The mean age of participants at start of therapy ranged from 9 to 12 years. Overall, we judged only one trial at low risk of bias in all domains and another trial at high risk of bias in most domains. We downgraded the level of evidence mainly because of imprecision (low number of trials, low number of participants or both). Comparing oxandrolone plus GH with GH only for final adult height showed a mean difference (MD) of 2.7 cm in favour of oxandrolone plus GH treatment (95% confidence interval (CI) 1.3 to 4.1; P < 0.001; 5 trials, 270 participants; moderate-quality evidence). The 95% prediction interval ranged between 0.3 cm and 5.1 cm. For adverse events, we based our main analysis on reliable date from two trials with overall low risk of bias. There was no evidence of a difference between oxandrolone plus GH and GH for adverse events (RR 1.81, 95% CI 0.83 to 3.96; P = 0.14; 2 trials, 170 participants; low-quality evidence). Six out of 86 (18.6%) participants receiving oxandrolone plus GH compared with 8/84 (9.5%) participants receiving GH only reported adverse events, mainly signs of virilisation (e.g. deepening of the voice). One trial each investigated the effects of treatments on speech (voice frequency; 88 participants), cognition (51 participants) and psychological status (106 participants). The overall results for these comparisons were inconclusive (very low-quality evidence). No trial reported on health-related quality of life or all-cause mortality. Addition of oxandrolone to the GH therapy led to a modest increase in the final adult height of girls aged up to 18 years with TS. Adverse effects identified included virilising effects such as deepening of the voice, but reporting was inadequate in some trials.

Plain-language summary: We included six randomised controlled trials (clinical trials where people are randomly put into one of two or more treatment groups). The duration of the treatments ranged between 3 and 7.6 years. Study authors allocated 498 participants to treatment groups, 267 participants to oxandrolone plus growth hormone treatment and 231 participants to growth hormone only treatment. The average age of the children at begin of treatment ranged from 9 to 12 years. This evidence is up to date as of October 2018. When comparing oxandrolone plus growth hormone to growth hormone only, the final adult height was on average 2.7 cm higher in favour of oxandrolone plus growth hormone therapy. Only two studies provided reliable data on side effects: 6 out of 86 (19%) participants given oxandrolone plus growth hormone compared with 8 out of 84 (10%) participants given growth hormone only reported side effects, mainly signs of development of male physical characteristics (for example deepening of the voice). One study investigated the effects of treatments on speech, the process of acquiring knowledge and understanding (cognition), and mental and emotional (psychological) status. The overall results for these were inconclusive. No trial measured people's satisfaction with their life and health or death from any cause. For side effects and effects on speech, cognition and psychological status, we are uncertain or very uncertain, mainly because the number of studies and participants was low and results were vague. For final adult height, we think that further research is likely to have an important impact on our confidence in the results and may change the results.