Turner syndrome (TS) is one of the common chromosomal abnormalities in girls. TS was initially described by Otto Ullrich in 1930 and later in 1938 by Henry Turner who described this syndrome in seven females with short stature, sexual infantilism, webbed neck and cubitus valgus (Turner 1938; Ullrich 1930). The incidence of TS is 1 in 2000 to 2500 female live births (Nielsen 1991; Pinsker 2012; Stochholm 2006). Most of the pregnancies with TS result in abortion. Gravholt et al studied the prevalence of TS karyotypes among prenatally tested fetuses and TS among liveborn infants in Denmark from 1970 to 1993 (Gravholt 1996). Their data showed that among female fetuses tested by amniocentesis, the prevalence of TS karyotypes was 176/100,000 while the prevalence was 392/100,000 among female fetuses tested by chorion villus sampling. These data proved that the prevalence of TS is not only influenced by testing during pregnancy or after birth but also depends on the method of prenatal testing (Gravholt 1996).
Description of the condition
TS is characterised by complete or partial loss of the second X chromosome (Nielsen 1991). Complete loss of one X chromosome (45 X) results in classical features of the disease while mosaics present with varying and generally lesser degrees of manifestation. Variable aberrations of the second X chromosome such as deletion, ring chromosome, and isochromosome cause phenotypic features of TS in 46 XX patients. The most frequent chromosomal abnormality in TS is 45 X (Nielsen 1991; Pinsker 2012; Stochholm 2006). The Danish TS registry showed that the 45 X karyotype was found in half of patients, followed by mosaics (Gravholt 1996).
TS is a multisystem disorder with the cardiovascular, skeletal, endocrine and reproductive systems mostly affected (Stochholm 2006). Lymphoedema of the hand and foot is an early sign of TS. Other dysmorphic features include widely spaced nipples, cubitus valgus, short webbed neck, low posterior hairline and narrow hyperconvex nails (Baxter 2007; Nielsen 1991; Pinsker 2012; Stochholm 2006). Congenital heart diseases are more frequent in individuals with TS compared to the general population (Stochholm 2006). The Italian study group for TS reported on cardiac anomalies in 594 patients with the disease (Mazzanti 1998). The prevalence of cardiac malformations in this study was 23%, with bicuspid aortic valve (12.5%), aortic coarctation (6.9%) and aortic valve disease (3.2%). Growth failure in childhood leading to short final adult height is the cardinal sign in girls with TS (Pinsker 2012; Stochholm 2006). While their birth weight is slightly impaired in utero, girls with TS may present early in childhood with failure to thrive (Davenport 1999). The height of patients with TS, when plotted on growth curves specific for this disorder, shows that growth velocity declinesbelow the reference growth curve for females often as early as two to four years of age (Saenger 1999). The adult height (defined as the height at which the epiphyses are closed or height velocity is less than 1 cm/year) of Turner patients is approximately 20 cm below that of the average female population. Naeraa and Nielsen studied growth parameters in 78 patients with TS (Naeraa 1990; Nielsen 1991). Analysis of the growth pattern showed that though no pubertal growth spurt was present, the steady decrease of height velocity (defined as increment in height per year in centimetres) was interrupted at the age of nine years. Height velocity was then constant until 12 years of age, thereafter it slowly decreased. The mean final height of this cohort was 146.8 cm (SD 5.8 cm, N = 76) compared to 166.8 cm in the general female population (Naeraa 1990). Therefore, short final adult height in TS is explained by poor childhood growth in addition to the lack of a pubertal growth spurt.
Hypergonadotrophic hypogonadism resulting from ovarian failure is a cardinal feature of TS. Primary infertility and lack of pubertal signs are seen in the vast majority of girls with TS (Bondy 2007). Spontaneous puberty and rarely pregnancy are reported in a minority of patients with TS, most of them carrying mosaic karyotype (Tracy 2011). Assisted reproduction remains an option to achieve pregnancy for women with primary ovarian failure including those with TS (Tracy 2011).
Characteristic neurocognitive features of TS include normal verbal function and impaired visual-spatial and perceptual abilities, attention, working memory, and spatially dependent executive function (Ross 2006). However, global developmental delay is uncommon in TS (Nielsen 1991; Pinsker 2012; Stochholm 2006). Short stature, delayed puberty and the presence of dysmorphic features contribute to the social and emotional impairment observed in TS (Ross 2006). Failure to treat growth and puberty stigmata may lead to further psychological and psychiatric problems (Bondy 2007; Carel 2006).
Description of the intervention
Growth hormone (GH) is a peptide hormone secreted by the anterior pituitary gland. GH promotes linear growth by stimulating production of insulin-like growth factor 1 that acts at the growth plate by enhancing differentiation of prechondrocytes and the expansion of osteoblasts (Reh CS 2010).
GH is currently used as a once-daily subcutaneous injection, typically given late in the evening to mimic the physiological secretory pattern of endogenous GH (Reh CS 2010). There is a wide range of recommended dosing of GH internationally for the treatment of growth-hormone deficiency. The dose of GH ranges between 0.5 to 0.7 IU/kg/week (0.17 to 0.23 mg/kg/week) in most countries (Tanaka 1999).
GH is generally safe with adverse events such as benign intracranial hypertension, slipped femoral epiphysis, worsening of scoliosis and impaired glucose homeostasis infrequently observed (Bell 2010; Wilton 1999).
Recombinant human GH was approved by the US Food and Drug Administration (FDA) for use in children with GH deficiency in 1985 and for TS in 1996. In the last three decades, multiple studies have confirmed the effectiveness and safety of GH therapy (Bell 2010; Reh CS 2010; Tanaka 1999; Takeda 2010).
Currently GH therapy is recommended for all children and adolescents with TS as the evidence supports this intervention (Baxter 2007; Canadian Growth Hormone Advisory Committee 2005; Takeda 2010). Standard management of TS entails starting GH in childhood to maximise height gain and to improve the final adult height (Bondy 2007; Davenport 2007; Ranke 2007; Stephure 2005). Furthermore, treatment with GH positively affects body composition by increasing muscle mass and decreasing fat mass (Gravholt 2002). A Cochrane systematic review investigated the effects of GH in children and adolescents with TS (Baxter 2007). Four randomised controlled trials (RCTs) that included 365 participants after one year of treatment were included. This systematic review concluded that GH increases short-term growth in girls with TS by approximately 3 cm in the first year of treatment and 2 cm in the second year. In one trial treatment increased final height by approximately 6 cm over the height in an untreated control group. The optimal age for initiation of GH therapy for young children has not been established. Davenport et al showed that early GH treatment can correct growth failure and normalize height in infants and toddlers with TS (Fechner 2007).
Carel et al carried out a population-based cohort study of health-related quality of life determinants in 568 young women with TS using the 'Medical Outcome Study Short Form 36' (SF-36) score and the 'General Health Questionnaire' 12 score (Carel 2005; Carel 2006). This study concluded that health-related quality of life is normal and unaffected by height in young adults with TS treated with GH. Similar results were reported by Taback et al who conducted a follow-up study on the health-related quality of life of young adults from a long-term controlled trial of GH treatment in patients with TS (Taback 2011). This study found no benefit or adverse effects on health-related quality of life either from receiving or not receiving GH injections in a long-term RCT.
The majority of patients with TS have delayed puberty leading to the lack of a pubertal growth spurt, which compromises the final adult height. Therefore oestrogen is commonly started on top of GH in order to induce puberty and maximize final adult height (Bondy 2007; Van Pareren 2003).
Oxandrolone (Ox) is an anabolic steroid (a synthetic derivative of testosterone). It is a weak androgen (Menke 2011) and is available in 2.5 mg and 10 mg tablets. The dose for children is weight based (0.1 mg/kg), however have been wide variations in the Ox dose (mostly 0.03 to 0.06 mg/kg/d) used in different studies investigating growth promotion in TS (Bareille 1997; Gault 2011; Job 1991; Joss 1984; Menke 2010; Nilsson 1996; Rosenfeld 1992; Stahnke 2002; Zeger 2011). Recently a stable and validated liquid formulation of oxandrolone has been developed. This formulation uses commercially available oxandrolone tablets which are crushed and dispersed in syrup (Garg 2011). Historically, Ox was initially approved in 1964 for treatment of wasting associated with conditions such as chronic infection, severe trauma, and after extensive surgery (Mann 1999). In the last two decades, Ox was used as an adjuvant therapy to promote healing in severe burning (Hart 2001; Sheffield-Moore 1999).
In order to improve growth, Ox is usually started a few years before the appropriate age for induction of puberty in girls with TS. Both GH and Ox are discontinued when the adult final height has been achieved (Bondy 2007; Stochholm 2006).
Adverse effects of the intervention
Adverse effects associated with Ox include signs of virilization such as clitoral enlargement, acne, lowering of the voice, and more rapid skeletal maturation (Carolyn 2007).
How the intervention might work
Although Ox is a known anabolic steroid, the exact mechanism by which Ox improves growth is unknown. It may act directly on the growth plate (Haeusler 1996; Sheffield-Moore 1999; Wilson 1998). The advantage of Ox over other growth promoting androgens is that it may improve the final adult height and at the same time does not promote bone maturation that leads to early fusion of the epiphysis (Bareille 1997; Gault 2011; Haeusler 1996; Job 1991; Joss 1984; Menke 2010; Nilsson 1996; Rosenfeld 1992; Stahnke 2002; Wilson 1998; Zeger 2011).
Why it is important to do this review
The use of Ox as an adjuvant therapy to GH aiming to maximize the final adult height is unclear. There is currently no published systematic review investigating the role of Ox in the management of girls with TS. Therefore, we would like to conduct a systematic review to evaluate the effects and safety of Ox in patients with TS already treated with GH. This will help physicians and health policy developers to make evidence-based recommendations regarding the role of Ox in TS.