Safety and Efficacy of Oxandrolone in Growth Hormone-Treated Girls with Turner Syndrome: Evidence from Recent Studies and Recommendations for Use

Virilization

The US study using Ox 0.06 mg/kg/day (with a maximum daily dose of 3.75 mg) showed subjective clitoral changes (2 girls on Ox and 2 on Pl), acne (1 on Ox) and mild hirsutism (3 on Ox) in patients after which the Ox/Pl dose was reduced [7]. The Dutch study showed that while there were sporadic complaints about virilization in the Pl group (5%), more girls in the Ox groups reported features of mild virilization (subjective voice deepening, hirsutism, and mild clitoromegaly). This was particularly evident in girls receiving Ox 0.06 mg/kg/day (with a maximum of 3.75 mg) (42%), and to a lesser extent in the group receiving Ox 0.03 mg/kg/day (16%) [4]. In addition, the objective deepening of the voice was greater in the groups receiving GH+Ox compared to those receiving GH+Pl [10]. One girl on Ox 0.03 and 7 on Ox 0.06 (vs. zero on Pl, p = 0.005) discontinued Ox because of virilization [4]. By contrast, the UK study (using 0.05 mg/kg/day with a maximum daily dose of 2.5 mg) did not report any virilizing effects [8].

It is at present unclear as to how the discrepancies in virilizing effects between the three studies can be explained. In the two studies using 0.06 mg/kg/day, virilization was noted in a substantial number of the girls [4,7]. In the US study, in which the study design included dose reduction, the Ox dose was reduced in about 40% of the girls because of virilization [7]. The absence of virilization in the UK study (using Ox 0.05 mg/kg/day) appears to show that this dose regimen does not lead to virilization. However, it should be noted that no systematic and specific assessment of possible virilization was carried out in this study in which investigators were simply asked to record any adverse event/reaction at each visit [8]. Another explanation may be the use of a relatively low maximal Ox dose in the UK study (2.5 mg/day) in comparison to maximum daily dose of 3.75 mg in the US and Dutch studies [4,7]. However, most girls reported virilization before they were receiving a daily dose >2.5 mg [unpubl. data from the Dutch study].

At present, long-term follow-up data are only available in the women who participated in the Dutch study. This follow-up study showed that even after an average period of 8.7 years, the number of girls who still subjectively experienced virilization was higher in the group that had received Ox compared to Pl [11]. There was also a trend towards a higher Ferriman-Gallwey hirsutism score with Ox (though the score was subclinical for most girls). Three girls who had received Ox still had objective clitoromegaly. In addition, the dose-dependent effect of Ox on lowering voice frequency, which was reported in the pediatric Dutch study [10], was also seen in the follow-up study [11]. However, only a few [7 of the 43 (16%) Ox-treated versus 2 of the 23 (9%) Pl-treated] patients had developed a voice frequency <-2 SDS; in most instances the voice frequency remained within the normal range. The percentage of patients reporting subjective voice deepening was similar between the GH+Ox and GH+Pl groups [11].

In conclusion, the addition of Ox (0.03-0.06 mg/kg/day) shows mild dose-dependent subjective and objective virilizing effects in girls with TS, which leads in some individuals to dose reduction or premature discontinuation of treatment. Although hirsutism and acne seem to regress after discontinuation of Ox, clitoromegaly and voice deepening appear irreversible.

Delay of Breast Development

In all three studies, estrogens were started approximately 2 years later than the average age of onset of puberty in the non-TS population (12.5 years – and in one arm of the UK study even 14 years – compared with 10.5 years in population studies) [12]. In the Dutch follow-up study, about 50% of the women had experienced their breast development as delayed, while in 24% the delay of breast development was accompanied by negative emotions or unhappy feelings [11]. In line with expectations based on previous observations [13], Ox therapy was associated with delayed breast development in the US study as well as in the Dutch studies [7,4] while this parameter was not monitored in the UK study [8]. In the US study, mean Tanner breast stage in the Ox group was approximately one stage behind that of the Pl group after 4 years. At follow-up, more patients who had received Ox had not achieved Tanner breast stage 5 than Pl-treated women [7]. In the Dutch study the increase in breast stage SDS was less with Ox 0.03 and 0.06 mg/kg/day treatment than with Pl in the first 2 years or with discontinuation of Ox/Pl [4]. However, the Dutch follow-up study showed no difference in the subjective experience of delay in breast development during puberty and adolescence between the treatment groups. In addition, the effect of Ox on breast development was transient since final breast size, measured as subtraction of the smallest chest circumference (under the breasts) from the widest chest circumference (at the level of the nipples) with the patient in supine position and Tanner breast stage, was similar in the Ox and Pl groups [11].

In conclusion, girls with TS receiving Ox undergo a delay in breast development, which disappears after several years on an adult estrogen replacement dose. The consequences of this transient side effect on the patients’ well-being in adolescence and adulthood are unknown.

Body Proportions and Body Composition

In the Dutch study there was a trend towards a higher sitting height using higher Ox doses compared to Pl. In addition, shoulder width was somewhat larger and hip width smaller in the Ox groups compared with the Pl group [14]. These findings were confirmed in the follow-up study, although the numerical difference did not reach statistical significance [11].

Regarding foot and hand length, previous reports have shown that the already relatively large foot and hand length of TS patients increase during GH treatment, with a possible additional effect in girls receiving a higher dose of GH [15,16]. There are no longitudinal data on the effect of Ox on hand and foot length. However, the Dutch follow-up study showed that the addition of Ox to the standard GH dose does not further increase the disproportion in foot or hand length compared with height. Head circumference was greater in both Ox-treated groups in comparison with Pl-treated girls, but the head circumference/height ratio was not different [11].

The US study found no differences in terms of change in weight SDS, body mass index SDS, and waist-to-hip ratio from baseline throughout the study between Ox and Pl [5]. In the Dutch study a reduction in fat mass and an increment in muscle mass during Ox treatment were found [14]. In the follow-up study, however, this effect of Ox on fat mass and muscle mass, measured using DEXA, was no longer observed [11]. Thus, the initial beneficial effects of Ox on body composition are transient. The UK study did not record data on body proportions or body composition [8].

In conclusion, the effects of Ox on body proportions (higher sitting height, broader shoulders) are mild and the effects on body composition appear to be transient.

Cardiovascular Risk

In the US study, high-density lipoprotein (HDL) cholesterol levels were lower in the Ox group from study visits at 6 months to 2 years, but then increased in the Ox group once estrogen replacement was begun so that there was less of a difference by year 4. There was no significant difference between groups in low-density lipoprotein (LDL) cholesterol measurements for any visit. Triglycerides were lower in the Ox group than in the Pl group at years 3 and 4 [7]. The Dutch study did not present longitudinal data on lipids [4], but lipid data were obtained at the follow-up study. Eight years after discontinuation of Ox/Pl, mean HDL cholesterol was (although within the normal range) significantly lower in the Ox-treated groups than in the Pl group [11]. This finding suggests that the effect of Ox on lipids is not transient and may be considered as sufficient reason to monitor these during treatment.

The Dutch study showed that at start of treatment, during treatment and after discontinuation of GH+Pl/Ox, mean systolic and diastolic blood pressure were significantly higher than in healthy girls, without significant differences between Ox dosage groups [4].

In the US and Dutch studies in which oral glucose tolerance tests were performed, the glucose and insulin levels were not significantly different between the Ox and Pl groups [7,11,17].

Bone Mineral Density

Previous studies in women with TS have shown that cortical bone mineral density is lower and the fracture risk is higher than in the normal population [18,19]. Bone health was not reported in the Dutch or UK paper. In the US study, Ox had no effect on bone mineral density SDS [7]. Bone health data have been collected as part of the Dutch follow-up study and are being analyzed at the present time. Such long-term data will be of importance in showing whether or not Ox increases bone density as an androgen-related effect.

IGF-1 Levels

In the US study, IGF-1 levels were similar between the Ox and Pl groups at baseline, lower in the Ox group from 6 months to 2 years, and again similar thereafter (when estrogen was added). Serum IGFBP-3 levels were similar in the Ox and Pl groups except for the baseline and 6-month visits [7]. In the Dutch study, IGF-1 SDS values were stable over time, although levels were more frequently increased on Ox than on Pl, whereas the increase in IGF-1 levels and IGF-1 to IGFBP-3 ratio (an indicator of free IGF-1) was not significantly different between the dosage groups [4]. Thus, there was no evidence for higher or lower IGF-1 levels following estrogen induction in these two studies. In the UK study, IGF-1 levels were not routinely assessed as part of the protocol.

Cognitive and Psychosocial Development

In the US study a small decrease in frequency of severe arithmetic learning disability after 4 years of Ox was observed [20]. In the Dutch study, behavior problems, frequently present in untreated girls with TS, decreased during therapy, but total and internalizing problem behavior remained increased, without differences between the Ox and Pl groups [21]. Ox treatment was not associated with any obvious psychological symptoms which could be attributable to virilizing side effects.

Optimal Age to Start Ox

The lowest age at which Ox was started in the three studies was 8 [4], 9 [8] and 10 [7] years, respectively. In view of the possible virilizing effect, starting Ox before the age of 8 years in doses between 0.03 and 0.06 mg/kg/day is not recommended. However, the effect of even lower Ox doses at <8 years of age has not been reported. Since many patients in the three studies were older than 8-10 years at the start of treatment, age at the start of Ox ranged from 8 to 16 years (for details, see table 1). In the Dutch study, no statistically significant difference in the effect of Ox on adult height gain was found between the three age groups [4]. Thus, in contrast to GH treatment, starting Ox therapy as young as 8 years does not appear to be more effective than starting later. Furthermore, it might be expected that possible virilizing side effects from Ox would result in a greater psychosocial burden in a younger girl with TS than in an older girl. In conclusion, adjunctive treatment with Ox appears effective in the age range of 8-16 years. However, starting Ox relatively young, e.g. before 8 years of age, does not seem to be more favorable than starting in the early pubertal age range.

Optimal Dose of Ox

In the US [7] and Dutch [4,11] studies, an Ox dose of 0.06 mg/kg/day with a relatively high maximum dose of 3.75 resulted in more virilization and increased skeletal maturation, and the efficacy was less than that of the lower dose (0.03 mg/kg/day) in the Dutch study [4]. Consequently, we believe that for most girls an Ox dose of 0.06 mg/kg/day is too high [22]. A dose of 0.05 mg/kg/day with a maximum of 2.5 mg/day appears to be effective and safe, as is the case with a dose of 0.03 mg/kg/day. The slightly higher adult height gain on Ox 0.05 mg/kg/day in the UK study [8] than on 0.03 mg/kg/day in the Dutch study [4] may be explained, at least partially, by the differences in baseline characteristics between the Ox and Pl groups (lower age at start in the Ox group in the UK study), and the later start of estrogens in 50% of the girls in the UK study [8]. An even lower Ox dose than 0.03 mg/kg/day has not yet been studied and could theoretically still have a positive effect on height with even fewer signs of virilization. However, the currently available evidence suggests that an Ox dose between 0.03 and 0.05 mg/kg/day offers the best benefit-risk ratio. As even on a dose of 0.03 mg/kg/day some virilization has been observed, patients and parents should be informed about these possible side effects before starting Ox. When these side effects occur, the dose should be decreased.

There is no scientific evidence to prove that a maximum daily dose for Ox should be set (2.5 mg in the UK study, 3.75 mg in the US and Dutch studies) [4,7,8]. In most girls the complaints about virilization started before they were receiving a daily dose of >2.5 mg [unpubl. data from the Dutch study]. Furthermore, if a dose of 0.03 mg/kg is given, most girls will never reach a dose >2.5 mg (given that few will surpass a body weight of 83 kg). However, we suggest that if an Ox dose of 0.03-0.05 mg/kg/day is prescribed, a pragmatic ceiling dose of 2.5 mg can be used to prevent overdosing, particularly in older and heavier girls.

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 [4], 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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