Sas T.C.J.a, b · Gault E.J.f · Zeger Bardsley M.g · Menke L.A.c · Freriks K.d · Perry R.J.f · Otten B.J.e · de Muinck Keizer-Schrama S.M.P.F.b · Timmers H.d · Wit J.M.c · Ross J.L.g · Donaldson M.D.C.f
There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3-4.6 cm. If Ox dosages <0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization (including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated, or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03-0.05 mg/kg/day starting from the age of 8-10 years onwards can be considered.
© 2014 S. Karger AG, Basel
While growth hormone (GH) has been shown to improve final height (FH) in Turner syndrome (TS), such treatment can only partially overcome the growth failure observed in affected girls. It is for this reason that adjunctive therapy in TS has been tried, notably with oxandrolone (Ox), a synthetic anabolic steroid derived from dihydrotestosterone by replacing the carbon atom in position 2 with an oxygen atom, and methylating the carbon atom in position 17. Ox treatment, when combined with GH, has been shown to increase height velocity in TS  and to improve FH [2,3], but its use has not become standard for two main reasons. Firstly, the patient numbers involved in previous studies reporting increased FH with GH and Ox have been relatively small. For example, Nilsson et al.  found FH to be greatest in girls receiving GH and Ox compared with GH ± ethinyl estradiol (EE2) and GH, Ox and EE2, but there were 15 or fewer girls in each of the three groups, while in the study of Stahnke et al.  only 7 girls treated with GH alone and 15 girls who had received GH and consistent Ox treatment were at FH. Secondly, features of virilization with clitoromegaly and voice deepening have been reported with Ox doses of 0.1 mg/kg/day or more, requiring a reduction in dosage [1,3]. Given these concerns, and because none of the above studies were placebo (Pl)-controlled, there has to date been insufficient information about both the efficacy and safety of Ox and the optimal dose and age at starting this treatment.
The recent publication of three randomized Pl-controlled, double-blind studies on the effects of Ox in addition to GH in girls with TS has generated more insight into the benefit-risk ratio of Ox [4,5,6].
In this paper we summarize the findings of the three recent studies [4,5,6] in terms of efficacy and safety, and present recommendations concerning the use of Ox in TS. We also draw attention to areas where our knowledge remains insufficient. Whilst a meta-analysis of the data from the three studies was carefully considered and would have the advantages of increasing sample size thus decreasing the confidence intervals, there are difficulties in applying this approach to our situation. Firstly, pooled analysis is usually more suited to situations where more than three studies are available for analysis. Secondly, there are considerable differences in Ox dosage and in timing of GH, Ox and estrogen treatment between the treatment regimens of the three studies. Finally, meta-analysis of the results of these three studies could obscure the influence of the various treatment regimens. For these reasons we have chosen to simply compare and contrast the results from each study.
Efficacy of Ox in GH-Treated Girls with TS
Safety of Ox in GH-Treated Girls with TS
In previous studies as well as in the three recent studies, various aspects of safety were assessed. Here we discuss virilization, delay of breast development, body proportions and composition, cardiovascular risk, bone mineral density, circulating IGF-1, and psychosocial aspects.
Conclusions on the Possible Role of Ox in TS
The three recent controlled studies have shown that the addition of Ox to GH treatment (starting at an age between 8 and 16 years) leads to an increase in height velocity and a modest increase of adult height, on average 2.3-4.6 cm, confirming the results of previous clinical trials. The effect of an adequate dose of GH alone on adult height is particularly dependent on the age at the start of GH ranging from approximately 6 cm in girls older than 8 years up to 10-12 cm in younger girls. Therefore, the additional effect of Ox can be estimated at 25-50%. The cost of 5 years of Ox treatment at an average dose of 2.5 mg is calculated at USD 6,000-7,000, although in practice many girls will receive lower doses than this. This cost is more than outweighed by the shorter duration of GH treatment if Ox is added, estimated at approximately EUR 10,000 (USD 13,700) when Ox 0.03 mg/kg/day is used , while the efficacy in terms of adult height is approximately 3 cm greater. Two possible additional benefits (as yet not proven) of adjunctive treatment with Ox may be an increase of cortical thickness and a redress of the relative androgen deficiency in adolescent girls with TS. Side effects are modest if dosages are <0.06 mg/kg/day. The most relevant safety concerns are virilization (including clitoromegaly and voice deepening), transient delay of breast development, and a decrease of HDL cholesterol, but side effects in the very long term are unknown. We advise that during Ox treatment subjective and objective signs of virilization, breast development, and blood lipids should be monitored. The laboratory costs of this are significant, estimated at USD 500 per year, but could be viewed as part of good practice in the monitoring of TS, whether or not adjunctive Ox is used. We believe that in girls with TS who are severely short for age, in whom very short adult stature is anticipated, or in whom the growth rate is modest despite good compliance with GH (as evidenced by normal/high IGF-1 levels), adjunctive treatment with Ox at a dosage of 0.03-0.05 mg/kg/day started from the age of 8-10 years onwards can be considered and discussed with the girl and her family.
H. Timmers received a research grant from Pfizer for this research. T.C.J. Sas received lecture fees from Novo Nordisk and Pfizer and did advisory work for Novo Nordisk. J.M. Wit has served on the advisory boards of Pfizer, Ipsen, Versartis, Prolor, and Biopartners and received fees from Pfizer, Ipsen, and Ferring. L.A. Menke received an honorarium for her thesis from Pfizer, Eli Lilly & Co., ACE Pharmaceuticals, Ferring, Novo Nordisk, Ipsen, and Sandoz. M.D.C. Donaldson received travel expenses from the British Society for Paediatric Endocrinology and Diabetes to attend study Steering Group meetings and royalties from endocrine textbook, consultancy fees for medicolegal reports, and lecture fees from endocrine symposia. E.J. Gault received financial support from the Scottish Executive Chief Scientist Office, the British Society for Paediatric Endocrinology and Diabetes and the Child Growth Foundation, travel expenses to attend an international meeting and a departmental honorarium for presenting preliminary results at a specialist nurse workshop, and travel expenses from the British Society for Paediatric Endocrinology and Diabetes to attend study Steering Group meetings. J.L. Ross has received grant support from Eli Lilly & Co., Pfizer, and Novo Nordisk and has served as a consultant for Eli Lilly & Co., Pfizer, and Novo Nordisk. M. Zeger Bardsley, R.J. Perry, K. Freriks, B.J. Otten and S.M.P.F. de Muinck Keizer-Schrama have nothing to disclose.
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