Spiliotis girls are usually far behind their peers in height for most of their childhood adding frequently to their psychosocial isolation (Siegel et al 1998). A recent study from the Toddler Turner Study has added greatly to our insight on the age of initiation of hGH therapy in TS (Davenport et al 2007). This trial initiated hGH therapy (0.35 mg/kg/week) in TS girls at 2 years of age even before a signiﬁcant deceleration in the height velocity was apparent. During the 2 years of therapy in these very young TS girls it was shown that there was a signiﬁcant increase in height SDS (+1.1 SDS) in the treated girls compared with the non-treated age-matched controls. There were no signiﬁcant differences between the bone ages of the two groups and as expected the IGF-I and IGFBP-3 levels increased in the hGH treated group within the normal concentrations for age. Following this study, it became apparent that the current thinking on the age of initiation of hGH therapy in girls with TS may need to be re-evaluated and new guidelines might need be instituted in order to pos- sibly recommend hGH therapy at an earlier age in the TS girls instead of waiting for the deceleration in growth which is standard in TS. With earlier hGH therapy the girls with TS might have a chance to avoid the psychosocial isolation during childhood associated with the severe growth impair- ment of TS. The age of the initiation of hGH therapy though is still a matter of debate and further studies are still needed to conclusively address this issue. Oxandrolone therapy In the initial randomized, multicenter trial which was ﬁrst reported in 1986, hGH was used alone or in combination with the androgen oxandrolone. After the completion of this trial, when the TS patients had attained their ﬁnal height, this combined therapy was shown to have a signiﬁcant impact on improving their growth and ﬁnal adult height (Rosenfeld et al 1986). The 17 TS girls who completed this initial trial with hGH alone (0.375 mg/kg/week) attained a ﬁnal height of 150.4 cm, which was 8.4 ± 4.5 cm above their projected adult heights. For the 43 TS girls treated with a combination of hGH (0.375 mg/kg/week) and oxandrolone (0.125 mg/kg/week), the mean adult height attained was 152.1 cm, which was 10.3 ± 4.7 cm taller than their projected adult heights (Rosenfeld et al 1998). Oxandrolone is not used very often currently since hormone replacement with estradiol in combination with hGH has been shown to be a more effective therapeutical regimen (Reiter et al 2001). Therapy using oxandrolone at a usual dose of 0.05 mg/kg/day is used mostly in TS patients with extreme short stature who start hGH therapy after 9 years of age. Therapy may 1180 be continued until a satisfactory height has been attained or until growth potential is limited (bone age 14 years and growth velocity 2 cm/year) (Bondy 2006). Estrogen therapy Most studies have shown that the ﬁnal height of girls with TS seems to be maximized when estrogen therapy is combined with hGH. The optimal age of the initiation of estrogen therapy is at a normal pubertal age around 12 years of age (Reiter et al 2001; Quigley et al 2002). This is in contrast to the view that had prevailed till recently that delaying estro- gen therapy till 15 years of age optimizes height potential (Rosenfeld et al 1986; Chernausek et al 2004). The reason for this dichotomy of views seems to be due to the fact that in some older studies younger TS girls were started on relatively large doses of conjugated estrogens in spite of the fact that it was clearly shown in 1983 that the effect of estradiol on growth has a biphasic effect, that is stimulatory at low doses and inhibitory at high doses (Ross et al 1983). The most current therapeutic trial of hGH and low-dose estrogen in TS girls, which had a duration of 20 years, decidedly showed that using very low doses of estradiol together with hGH at a normal pubertal age mimicking more closely the estrogen levels present in healthy girls at the time of puberty and increasing the estradiol dose as the TS girl progresses through puberty has a greatly enhancing effect on ﬁnal adult height (Ross et al 2007). While early studies indicated that delaying estrogen replacement could improve ﬁnal height outcomes in TS patients receiving hGH, this is not usually recommended, as delaying puberty in individuals who may already have a poor self-image may put them at a greater psycho-social disadvantage (Rosenfeld 2007). Start- ing estradiol at approximately 12 years of age also allows the TS girls to attain a normal bone mass which can only be attained if estradiol is started at the normal age of puberty and continued throughout puberty and adulthood (Hogler et al 2004). Health-related quality of life (HRQoL) evaluations of young women with TS who were treated long-term with hGH and sex steroid hormonal replacement therapy (HRT) showed that the women who had reached normal height and who had age-appropriate pubertal development had high scores on the HRQoL scales including “social functioning” and “role-emotional” scales (Bannink et al 2006b). Many forms of estrogen are available for treating TS patients but oral estrogens have been most often used. Studies though show that transdermal and injectable depot forms of estradiol may be more physiologic alternatives to oral therapy (Ankarberg-Lindgren et al 2001; Piippo et al 2004; Therapeutics and Clinical Risk Management 2008:4(6)