Oxandrolona para las niñas tratadas con hormona del crecimiento de hasta 18 años con síndrome de Turner
Resumen
Antecedentes
La estatura final en la adultez de las niñas no tratadas de hasta 18 años con síndrome de Turner (ST) es aproximadamente 20 cm menor en comparación con las mujeres sanas. El tratamiento con hormona del crecimiento (HC) aumenta la estatura en la adultez de las pacientes con ST. Los efectos del agregado del andrógeno oxandrolona al tratamiento con HC son inciertos. Por lo tanto, se realizó esta revisión sistemática para investigar los efectos beneficiosos y perjudiciales de la oxandrolona como tratamiento coadyuvante para las pacientes con ST tratadas con HC.
Objetivos
Evaluar los efectos de la oxandrolona sobre las niñas tratadas con hormona del crecimiento de hasta 18 años con síndrome de Turner.
Métodos de búsqueda
Se hicieron búsquedas en CENTRAL, MEDLINE, Embase, el ICTRP Search Portal y ClinicalTrials.gov. La fecha de la última búsqueda fue octubre de 2018. We applied no language restrictions.
Criterios de selección
Se incluyeron ensayos clínicos controlados aleatorizados (ECA) que reclutaron a niñas de hasta 18 años de edad con ST que fueron tratadas con HC y oxandrolona en comparación con el tratamiento con HC solamente.
Obtención y análisis de los datos
Tres autores de la revisión, de forma independiente, examinaron la relevancia de los títulos y los resúmenes, seleccionaron los ensayos, extrajeron los datos y evaluaron el riesgo de sesgo. Los desacuerdos se resolvieron por consenso o mediante consulta con un cuarto autor de la revisión. La certeza general de la evidencia de los ensayos se evaluó mediante el uso del instrumento GRADE.
Resultados principales
Se incluyeron seis ensayos con 498 participantes con ST, 267 participantes fueron asignadas al azar a la oxandrolona más tratamiento con HC y 231 participantes fueron asignadas al azar al tratamiento con HC solamente. El tamaño de la muestra de los ensayos individuales varió entre 22 y 133 participantes. Los ensayos incluidos se realizaron en 65 centros sanitarios de endocrinología pediátrica diferentes, que incluyeron clínicas, centros, hospitales y universidades de EE.UU. y Europa. La duración de las intervenciones varió entre 3 y 7,6 años. La media de edad de las participantes al inicio del tratamiento varió de 9 a 12 años. En general, solo se evaluó un ensayo como en riesgo bajo de sesgo en todos los dominios y otro ensayo como en riesgo alto de sesgo en la mayoría de los dominios. Se redujo el nivel de la evidencia principalmente debido a la imprecisión (número reducido de ensayos, número escaso de participantes o ambos).
La comparación de la oxandrolona más HC versus HC solamente para la estatura final en la adultez mostró una diferencia de medias (DM) de 2,7 cm a favor del tratamiento con oxandrolona más HC (intervalo de confianza [IC] del 95%: 1,3 a 4,1; p < 0,001; 5 ensayos, 270 participantes; evidencia de calidad moderada). El intervalo de predicción del 95% osciló entre 0,3 cm y 5,1 cm. Para los eventos adversos, el análisis principal se basó en datos confiables de dos ensayos en riesgo bajo de sesgo general. No hubo evidencia de una diferencia entre la oxandrolona más HC y la HC en cuanto a los eventos adversos (CR 1,81; IC del 95%: 0,83 a 3,96; p = 0,14; 2 ensayos, 170 participantes; evidencia de calidad baja). Seis de 86 (18,6%) participantes que recibieron oxandrolona más HC en comparación con 8/84 (9,5%) participantes que recibieron HC solamente informaron eventos adversos, principalmente signos de virilización (p.ej. agravamiento de la voz). Un ensayo investigó los efectos de los tratamientos sobre el habla (frecuencia vocal; 88 participantes), uno sobre la cognición (51 participantes) y uno sobre el estado psicológico (106 participantes). Los resultados generales de estas comparaciones fueron no concluyentes (evidencia de calidad muy baja). Ningún ensayo informó de la calidad de vida relacionada con la salud ni de la mortalidad por todas las causas.
Conclusiones de los autores
El agregado de oxandrolona al tratamiento con HC dio lugar a un aumento modesto en la estatura final en la adultez en las niñas de hasta 18 años de edad con ST. Los efectos adversos identificados incluyeron efectos virilizantes como agravamiento de la voz, aunque el informe fue inadecuado en algunos ensayos.
PICO
Resumen en términos sencillos
Oxandrolona para las niñas tratadas con hormona del crecimiento de hasta 18 años con síndrome de Turner
Pregunta de la revisión
¿Cuáles son los efectos de la administración de oxandrolona a las niñas tratadas con hormona del crecimiento de hasta 18 años con síndrome de Turner?
Antecedentes
El síndrome de Turner es un trastorno genético que se presenta en niñas con una anomalía cromosómica en la que se observa una falta o un cambio en la totalidad o en parte de uno de los dos cromosomas X. El síndrome de Turner muestra varios signos y síntomas, entre ellos, estatura baja. El fracaso del crecimiento en la infancia, que da lugar a una estatura final baja en la edad adulta, contribuye al deterioro social y emocional. Si no reciben tratamiento, las niñas con síndrome de Turner presentan una estatura aproximadamente 20 cm más reducida que las jóvenes sanas. El tratamiento de las niñas con síndrome de Turner con hormona del crecimiento aumenta la estatura en la adultez. Se deseaba averiguar si el agregado de oxandrolona mejoraría aún más la estatura final en la adultez y los efectos de esta combinación sobre otros síntomas. La oxandrolona es un andrógeno. Los andrógenos son hormonas sexuales masculinas esenciales y también son importantes para las mujeres.
Características de los estudios
Se incluyeron seis ensayos controlados aleatorizados (ensayos clínicos en los que los participantes son asignados al azar a uno de dos o más grupos de tratamiento). La duración de los tratamientos varió entre 3 y 7,6 años. Los autores de los estudios asignaron a 498 participantes a los grupos de tratamiento, 267 participantes al tratamiento con oxandrolona más hormona del crecimiento y 231 participantes al tratamiento con hormona del crecimiento sola. La edad promedio de las niñas al inicio del tratamiento varió de 9 a 12 años.
Esta evidencia está actualizada hasta octubre de 2018.
Resultados clave
Al comparar oxandrolona más hormona del crecimiento con hormona del crecimiento sola, la estatura final en la adultez fue de un promedio de 2,7 cm mayor a favor de del tratamiento con oxandrolona más hormona del crecimiento. Solo dos estudios proporcionaron datos fiables sobre los efectos secundarios: 6 de 86 (19%) participantes a las que se les administró oxandrolona más hormona del crecimiento en comparación con 8 de 84 (10%) participantes a las que se les administró hormona del crecimiento sola informaron efectos secundarios, principalmente signos de desarrollo de características físicas masculinas (por ejemplo, agravamiento de la voz). Un estudio investigó los efectos de los tratamientos en el habla, el proceso de adquisición de conocimiento y la comprensión (cognición) y el estado mental y emocional (psicológico). Los resultados generales relacionados con lo anterior no fueron concluyentes. Ningún ensayo midió la satisfacción de las pacientes con la vida y la salud ni la muerte por cualquier causa.
Calidad de la evidencia
Los efectos secundarios y los efectos sobre el habla, la cognición y el estado psicológico se desconocen o son muy inciertos, principalmente debido a que el número de estudios y participantes fue bajo y los resultados fueron imprecisos. Para la estatura final en la adultez, se considera que es probable que la investigación adicional tenga un impacto importante en la confianza en los resultados y pueda cambiar los resultados.
Authors' conclusions
Summary of findings
| Oxandrolone for growth hormone‐treated girls aged up to 18 yearswith Turner syndrome | ||||||
| Patient: girls aged up to 18 years with Turner syndrome Settings: mostly paediatric endocrine centres Intervention: oxandrolone + growth hormone Comparison: growth hormone alone | ||||||
| Outcomes | Growth hormone | Oxandrolone + growth hormone | Relative effect | No of participants | Certainty of the evidence | Comments |
| Improvement in final adult height (cm) Follow‐up: 3–10 years | The mean final adult height ranged across control groups from 149.6 cm to 155.6 cm | The mean final adult height in the intervention groups was 2.7 cm higher (1.3 cm higher to 4.1 cm higher) | — | 270 (5) | ⊕⊕⊕⊝ | 95% prediction interval 0.3–5.1 cm |
| Adverse events (N) Follow‐up: 3–10 years | 95 per 1000 | 172 per 1000 (79 to 377) | RR 1.81 (0.83 to 3.96) | 170 (2) | ⊕⊕⊝⊝ | Data based on 2/4 trials with overall low risk of bias for adverse events. |
| Health‐related quality of life | Not reported | Follow‐up study with < 50% of initially randomised participants showed inconclusive results comparing oxandrolone + GH for total and mean scores (3 questionnaires). | ||||
| Effects on speech (voice frequency) Follow‐up: 6 years | See comment | 88 (1) | ⊕⊝⊝⊝ | Most voice frequencies remained within the normal range, but became occasionally lower, especially with oxandrolone + GH 0.06 mg/kg/day; results were inconclusive for oxandrolone + GH 0.03 mg/kg/day. | ||
| Effects on cognition Follow‐up: 2 years | See comment | 51 (1) | ⊕⊝⊝⊝ | Summary scores for working memory, spatial cognition, executive function and verbal abilities using the WISC‐R; after 2 years, comparison of oxandrolone + GH vs GH showed inconclusive results. | ||
| Effects on psychological status Follow‐up: 6 years | See comment | 106 (1) | ⊕⊝⊝⊝ | There were no evident psychological virilising effects in the area of behaviour, aggression, romantic and sexual interest, mood and gender role. | ||
| All‐cause mortality | Not reported | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level because of imprecision (low median sample size) – for details, see Appendix 15. | ||||||
Background
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 1 in 2500 female live births (Nielsen 1991; Pinsker 2012; Stochholm 2006). Most of the pregnancies with TS result in abortion. Gravholt and colleagues studied the prevalence of TS karyotypes among antenatally 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 antenatal 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 people with 46 XX (Mohamed 2015a). 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 the cohort, 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 people with TS compared to the general population (Stochholm 2006). One Italian study group for TS reported on cardiac anomalies in 594 people with the disease (Mazzanti 1998). The prevalence of cardiac malformations in this cohort 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 girls with TS, when plotted on growth curves specific for this disorder, shows that growth velocity declines below 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 people with TS is approximately 20 cm below that of the average female population. Naeraa and Nielsen studied growth parameters in 78 females with TS (Naeraa 1990; Nielsen 1991). They found that though there was no pubertal growth spurt, 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 (standard deviation (SD) 5.8 cm, 76 females) 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.
Hypergonadotropic hypogonadism resulting from ovarian failure is a cardinal feature of TS. Primary infertility and lack of pubertal signs are seen in most girls with TS (Bondy 2007a). Spontaneous puberty and rarely pregnancy are reported in some women with TS, most of them carrying mosaic karyotype (Hadnott 2011; Mohamed 2015b). Assisted reproduction remains an option to achieve pregnancy for women with primary ovarian failure including those with TS (Hadnott 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; Ross 2009; 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 2007a; Carel 2006; Menke 2010).
Description of the intervention
Growth hormone
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 (Ranke 1999; Reh CS 2010). There is a wide range of recommended dosing of GH for the treatment of GH deficiency. The standard dose of classical GH deficiency ranges between 0.5 IU/kg/week and 0.7 IU/kg/week (0.17 mg/kg/week and 0.23 mg/kg/week) in most countries (Tanaka 1999). As GH is usually not deficient in people with TS, higher doses have been used for augmenting growth in TS (Bell 2010; Reh CS 2010; Takeda 2010; 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).
Recombinant human GH was approved by the US Food and Drug Administration (FDA) for use in children with GH deficiency in 1985 and for girls with TS in 1996. Since the late 1980s, multiple studies have confirmed the efficacy and safety of GH therapy (Bell 2010; Reh CS 2010; Takeda 2010; Tanaka 1999).
Currently, GH therapy is recommended for all girls aged up to 18 years 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 2007a; Davenport 2007; Ranke 2007; Stephure 2005). Furthermore, treatment with GH positively affects body composition by increasing muscle mass and decreasing fat mass (Gravholt 2002). One Cochrane systematic review investigated the effects of GH in girls aged up to 18 years with TS (Baxter 2007). It included four randomised controlled trials (RCTs) with 365 participants receiving GH for at least one year. This review concluded that GH increased 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 compared with the height in an untreated control group (Baxter 2007). The optimal age for initiation of GH therapy for young girls has not been established. Davenport and colleagues showed that early GH treatment can correct growth failure and normalise height in infants and toddlers with TS (Davenport 2007).
Carel and colleagues 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 trial concluded that health‐related quality of life was normal and unaffected by height in young adults with TS treated with GH. Taback and colleagues found similar results in a follow‐up study on the health‐related quality of life of young adults from a long‐term controlled trial of GH treatment in participants with TS (Taback 2011). The trial found no benefit or adverse effects on health‐related quality of life either from receiving or not receiving GH injections.
Most people 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 with GH to induce puberty and maximise final adult height (Bondy 2007a; Van Pareren 2003).
The age of starting oestrogen in girls aged up to 18 years with TS, as well as the dose and the duration of therapy, varies considerably among physicians (Bondy 2007a; Pinsker 2012; Van Pareren 2003).
Oxandrolone
Oxandrolone is an anabolic steroid (a synthetic derivative of testosterone). It is a weak androgen (Menke 2010), and is available in 2.5 mg and 10 mg tablets. The dose for children is based on bodyweight (0.1 mg/kg); however, studies have used a variable oxandrolone dose (mostly 0.03 mg/kg/day to 0.06 mg/kg/day) to promotion growth in TS (Bareille 1997; Freriks 2012; Freriks 2015; Gault 2011; Job 1991; Joss 1984; Menke 2010; Nilsson 1996; Rosenfeld 1986; Rosenfeld 1987; Rosenfeld 1988; Rosenfeld 1989; Rosenfeld 1990; Rosenfeld 1992; Stahnke 1992; Stahnke 2002; Zeger 2011). 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, oxandrolone was initially approved in 1964 for treatment of wasting associated with conditions such as chronic infection, severe trauma and after extensive surgery (Mann 1999). Since the late 1990s, oxandrolone has been used as an adjuvant therapy to promote healing in severe burns (Hart 2001; Sheffield‐Moore 1999).
In order to improve growth, oxandrolone is usually started a few years before the appropriate age for induction of puberty in girls with TS. Both GH and oxandrolone are discontinued when the adult final height has been achieved (Bondy 2007a; Sas 2014; Stochholm 2006).
Adverse effects of the intervention
Adverse effects associated with oxandrolone include signs of virilisation such as clitoral enlargement, acne, lowering of the voice and more rapid skeletal maturation (Bondy 2007b; Menke 2011a; Menke 2011b; Rosenfeld 1998).
How the intervention might work
Although oxandrolone is a known anabolic steroid, the exact mechanism by which oxandrolone improves growth is unknown. It may act directly on the growth plate (Haeusler 1996; Sheffield‐Moore 1999; Wilson 1988). The advantage of oxandrolone over other growth‐promoting androgens is that it may improve the final adult height while not promoting bone maturation that leads to early fusion of the epiphysis (Bareille 1997; Ferrández 1989; Gault 2011; Haeusler 1996; Job 1991; Joss 1984; Joss 1997; Menke 2010; Nilsson 1996; Rosenfeld 1992; Sheanon 2015; Stahnke 2002; Zeger 2011).
Why it is important to do this review
The effects of oxandrolone as an adjuvant therapy to GH aiming to maximise the final adult height is unclear. Therefore, we conducted this systematic review to evaluate the effects and safety of oxandrolone in girls with TS already treated with GH. This will help physicians and health policy developers to make evidence‐based recommendations regarding the role of oxandrolone in TS.
Objectives
To assess the effects of oxandrolone on growth hormone‐treated girls aged up to 18 years with Turner syndrome.
Methods
Criteria for considering studies for this review
Types of studies
We included RCTs.
Types of participants
GH‐treated girls aged up to 18 years with TS.
Diagnostic criteria
As some people with TS lack the clinical phenotype suggestive of the disease, all participants in this review had their diagnosis of TS confirmed by a chromosomal study. This included complete (45 X) or partial loss of the second X chromosome (such as deletion, ring chromosome and isochromosome). Mosaics were also included. We included trials that enrolled some participants with TS who had an abnormal Y chromosome.
Types of interventions
All participants received GH treatment for at least one year. All other concurrent therapies were comparable between the intervention and comparator groups.
Intervention
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Oxandrolone plus GH treatment.
Comparator
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GH treatment only.
Minimum duration of intervention
Minimum duration of intervention was one year.
Summary of specific exclusion criteria
We excluded trials including participants diagnosed on clinical grounds without confirmation from chromosomal studies.
Types of outcome measures
We did not exclude a trial if it failed to report one or several of our primary or secondary outcome measures. If the trial reported none of our primary or secondary outcomes, we planned not to include the trial but wanted to provide some basic information in the 'Characteristics of awaiting classification' table.
Primary outcomes
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Improvement in final adult height.
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Health‐related quality of life.
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Adverse events.
Secondary outcomes
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Increase in height velocity.
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All‐cause mortality.
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Bone maturation.
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Effects on cognition.
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Effects on psychological status.
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Effects on speech.
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Socioeconomic effects.
Method and timing of outcome measurement
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Improvement in final adult height: defined as the height at which epiphyses were closed or height velocity was less than 2 cm per year (Bondy 2007a; Stochholm 2006), and measured after the expected age of normal female puberty.
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Health‐related quality of life: evaluated by a validated instrument such as the SF‐36 (Carel 2005; Carel 2006), and measured after the completion of the RCT.
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Adverse events: such as virilisation effects on hair distribution, deepening of voice, clitromegaly and measured during or after completion of the RCT.
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Increase in height velocity (in girls who had not reached their final adult height): height velocity is defined as increment in height per year in centimetres and measured before participants achieved their final adult height.
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All‐cause mortality: defined as death from any cause and measured during and at the end of the RCT.
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Bone maturation: assessed by X‐ray of the left hand for bone age and closure of the epiphysis and measured in years during and at the end of the RCT.
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Effects on cognition: measured using a validated instrument such as the Wechsler Intelligence Scale for Children Third Edition (WISC) (Wechsler 1991).
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Effects on psychological status: measured by a validated instrument such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) (Conway 2012), and measured after completion of the RCT.
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Effects on speech: assessed by speaking fundamental frequency (Andersson‐Wallgren 2008), and measured during or after completion of the RCT.
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Socioeconomic effects: defined as the impact of the disease on social and economic parameters such as education, marriage, employment and income, housing, equity and overall social well‐being. Socioeconomic effects were measured after completion of the RCT.
Search methods for identification of studies
Electronic searches
We searched the following sources from inception of each database to the specified date and placed no restrictions on the language of publication (Lefebvre 2011).
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Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9; searched 10 October 2018).
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Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily (from 1946 to 9 October 2018; searched 10 October 2018).
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Embase (from 1974 to 2015 week 32; searched 13 August 2015*).
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ClinicalTrials.gov (searched 10 October 2018).
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/trialsearch/; searched 10 October 2018).
*RCTs indexed in Embase are now prospectively added to CENTRAL via a highly sensitive screening process (Cochrane 2018) (used for Embase after August 2015).
For detailed search strategies, see Appendix 1. We continuously applied an email alert service for MEDLINE via OvidSP to identify newly published trials using the search strategy detailed in Appendix 1. If we detected additional relevant key words during any of the electronic or other searches, we modified the electronic search strategies to incorporate these terms and documented the changes. We placed no restrictions on the language of publication when searching the electronic databases or reviewing reference lists of identified trials.
Searching other resources
We tried to identify other potentially eligible trials or ancillary publications by searching the reference lists of included trials, systematic reviews, meta‐analyses and health technology assessment reports.
We defined grey literature as records detected in ClinicalTrials.gov or WHO ICTRP. In addition, we searched manufacturers' websites and databases from regulatory agencies (European Medicines Agency (EMA) and US FDA) (Hart 2001; Schroll 2015).
We did not use abstracts or conference proceedings for data extraction unless full data were available from trial authors because this information source does not fulfil the CONSORT requirements which consist of "an evidence‐based, minimum set of recommendations for reporting randomized trials" (CONSORT 2016; Scherer 2007). We planned to present information on abstracts or conference proceedings in the 'Characteristics of studies awaiting classification' table.
Data collection and analysis
Selection of studies
Three review authors (SM, YA, KA) independently scanned the abstract, title, or both, of every record retrieved by the literature searches, to determine which trials we should assessed further. We investigated the full‐text of all potentially relevant records. We resolved disagreements through consensus or by recourse to a fourth review author (YSM). If resolving disagreement was not possible, we categorised the trial as a 'Study awaiting classification' and we contacted trial authors for clarification. We presented an adapted PRISMA flow diagram to show the process of trial selection (Liberati 2009). We listed all articles excluded after full‐text assessment in a 'Characteristics of excluded studies' table and provided the reasons for exclusion.
Data extraction and management
For trials that fulfilled the inclusion criteria, three review authors (SM, HA, YSA) independently extracted key participant and intervention characteristics. We reported data on efficacy outcomes and adverse events using standard data extraction forms from the Cochrane Metabolic and Endocrine Disorders (CMED) Group. We resolved any disagreements by discussion, or, if required, by a fourth review author (YA) (for details see Characteristics of included studies table; Table 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 14; Appendix 15).
| Study ID | Intervention(s) and comparator(s) | Description of power and sample size calculation | Screened/eligible | Randomised | Analysed | Finishing trial | Randomised finishing trial | Follow‐up |
| (parallel RCT) | I: oxandrolone + GH | Sample size was estimated for height velocity: 60 girls (30 per group) yielded a > 95% probability to detect a statistically significant difference in height velocity between the GH + oxandrolone and GH + placebo groups at year 2. 70 girls completed the initial 2 years, thereafter 35 girls receiving oxandrolone and 31 girls receiving placebo chose to continue in the 2‐year double‐blind extension study (47 girls completed this phase and were evaluated at the end of year 4). | NR/76 | 40 | 37 | 37 (24 extension period) | 93 (60 extension period) | 2 years (2 years) |
| C: GH + placebo | 36 | 33 | 33 (23 extension period) | 92 (64 extension period) | ||||
| Total: | 76 | 70 | 70 (47 extension period) | 92 (62 extension period) | ||||
| (parallel factorial RCT) | I: oxandrolone + GH | Assuming an SD of 5 cm, 50 girls were needed in each group to detect a difference between groups in mean final height (defined as height velocity < 1 cm/year and bone age ≥ 15.5 years) of 2.8 cm with 80% power at 5% significance; total of 100 participants. | NR/106 | 51 | NA | NA | NA | Unclear (15 years) |
| C: GH + placebo | 55 | NA | NA | NA | ||||
| Total: | 106 | NA | NA | NA | ||||
| (parallel RCT) | I1: oxandrolone 0.03 mg/kg/day + GH | 15 girls per dosage and age group were needed to achieve a power of 80% to detect a difference (P = 0.05, 2 sided) in first‐year height velocity of 2 cm with an assumed SD of 2.6. ITT analyses were performed and differences in adult height gain were also assessed by a PP analysis. | NR/184 | 46 | 42 (ITT) | NA | NA | 1 year (2 years) |
| I2: oxandrolone 0.06 mg/kg/day + GH | 39 | 36 (ITT) | NA | NA | ||||
| C: GH + placebo | 48 | 42 (ITT) | NA | NA | ||||
| Total: | 133 | 120 (ITT) | NA | NA | ||||
| (parallel RCT) | I1: oxandrolone + GH | — | NR/91 | 44 (33) | NA | NA | NA | Initial phase: 12 months (2 years; 4 years; 5 years) |
| I2: transient oxandrolone + GH | 0 (38) | NA | NA | NA | ||||
| C: GH | 47 (20) | NA | NA | NA | ||||
| Total: | 91 (53) | NA | NA | NA | ||||
| (parallel RCT/CCT after 1–2 years) | I1: oxandrolone | — | NR/70e | 18 | NA | NA | NA | 12–24 months (3–6 years) |
| I2: oxandrolone + GH | 17 | |||||||
| C1: GH | 17 | |||||||
| C2: no treatment | 18 | |||||||
| total: | 70 | NA | NA | NA | ||||
| (parallel RCT) | I: oxandrolone + GH | — | NR/22 | 12 | 12 | 12 | 100 | 3 years |
| C: GH | 10 | 10 | 10 | 100 | ||||
| Total: | 22 | 22 | 22 | 100 | ||||
| Overall total | All interventions All comparators All interventions and comparators | 267 | — | |||||
| 231 | ||||||||
| 498 | ||||||||
aFollow‐up under randomised conditions until end of trial (= duration of intervention + follow‐up postintervention or identical to duration of intervention); extended follow‐up refers to follow‐up of participants once the original trial was terminated as specified in the power calculation.
bTwo years' double‐blind extension study, original trial duration 2 years.
cTwo by two factorial design: participants were randomised to oxandrolone or placebo from 9 years of age until final height; those with evidence of ovarian failure at 12 years were further randomised to oral ethinylestradiol or placebo; participants who received placebo and those recruited after the age of 12.3 years started ethinylestradiol at age 14; "in 2004 and 2008, the sole European manufacturer of oxandrolone 2.5 mg ceased production, resulting in 34 participants in 2004 and 11 in 2008 temporarily suspending active oxandrolone treatment (mean duration: 2004, 52 days; 2008, 163 days). In 2008, the decision was taken to terminate the treatment arm forthwith, resulting in eight participants stopping oxandrolone treatment prematurely."
d68 women (GH plus placebo: 23; oxandrolone 0.03 mg plus GH: 27; oxandrolone 0.06 mg plus GH: 18) participated in a follow‐up study (all participants and investigators remained blinded for the study medication, mean age was 24 years, mean time since stopping oxandrolone plus GH was 8.7 years); see Freriks 2012 under Menke 2010.
eFirst 12 months: oxandrolone plus GH versus GH only therapy.
fInitial 6 months observation period before randomisation; 70 girls admitted to trial, 67 girls completed the first trial year, 65 girls completed 3 years, 62 girls completed 3–6 years; at the end of an initial period of 12–20 months, girls in the original control and oxandrolone groups were given combination therapy of GH plus oxandrolone.
C: comparator; CCT: controlled clinical trial; GH: growth hormone; I: intervention; ITT: intention‐to‐treat; N: number; NA: not applicable; NR: not reported; PP: per protocol; RCT: randomised controlled trial; SD: standard deviation.
We provided information, including trial identifier for potentially relevant ongoing trials in the Characteristics of ongoing studies table and Appendix 7 ('Matrix of trial endpoints (publications and trial documents)'). We tried to find the protocol of each included trial and reported in Appendix 7 primary, secondary and other outcomes in comparison with data in publications.
We emailed all authors of included trials to enquire whether they were willing to answer questions regarding their trials. Appendix 14 shows the results of this survey. We sought relevant missing information on the trial from the primary trial authors, if required.
Dealing with duplicate and companion publications
In the event of duplicate publications, companion documents or multiple reports of a primary trial, we maximised the information yield by collating all available data and used the most complete data set aggregated across all known publications. We listed duplicate publications, companion documents, multiple reports of a primary trial, and trial documents of included trials (such as trial registry information) as secondary references under the study ID of the included trial.
Data from clinical trials registers
If data from included trials were available as study results in clinical trial registries, such as ClinicalTrials.gov or similar sources, we made full use of this information and extracted the data. If there was also a full publication of the trial, we collated and critically appraised all available data. If an included trial was marked as a completed trial in a clinical trial registry but no additional information (study results, publication, or both) was available, we planned to ad this trial to the 'Characteristics of studies awaiting classification' table.
Assessment of risk of bias in included studies
Three review authors (SM, HA, YSA) independently assessed the risk of bias of each included trial. We resolved disagreements by consensus or by consulting a fourth review author (YA). In cases of disagreement, we consulted the remainder of the review author team and made a judgement based on consensus. If adequate information was unavailable from the publications, trial protocols or other sources, we contacted the trial authors for more detail to request missing data on 'Risk of bias' items.
We used the Cochrane 'Risk of bias' assessment tool assigning assessments of low, high, or unclear risk of bias (see Appendix 2; Appendix 3; Higgins 2011a; Higgins 2017). We evaluated individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions, according to the criteria and associated categorisations contained therein(Higgins 2017).
Summary assessment of risk of bias
We presented a 'Risk of bias' graph and a 'Risk of bias' summary figure.
We distinguished between self‐reported and investigator‐assessed and adjudicated outcome measures.
We considered the following self‐reported outcomes.
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Health‐related quality of life.
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Adverse events.
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Effects on cognition.
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Effect on psychological status.
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Effects on speech.
We considered the following endpoints to be investigator‐assessed.
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Increment in height velocity and final adult height.
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Adverse events.
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All‐cause mortality.
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Bone maturation.
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Effects on cognition.
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Effect on psychological status.
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Effects on speech.
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Socioeconomic effects.
Risk of bias for a trial across outcomes
Some risk of bias domains such as selection bias (sequence generation and allocation sequence concealment) affect the risk of bias across all outcome measures in a trial. In case of high risk of selection bias, all endpoints investigated in the associated trial were marked as 'high' risk. Otherwise, we did not perform a summary assessment of the risk of bias across all outcomes for a trial.
Risk of bias for an outcome within a trial and across domains
We assessed the risk of bias for an outcome measure including all of the entries relevant to that outcome (i.e. both trial‐level entries and outcome‐specific entries). 'Low' risk of bias was defined as low risk of bias for all key domains, 'unclear' risk of bias as unclear risk of bias for one or more key domains and 'high' risk of bias as high risk of bias for one or more key domains.
Risk of bias for an outcome across trials and across domains
These are our main summary assessments that were incorporated in our judgements about the certainty of the evidence in the 'Summary of finding' tables. 'Low' risk of bias was defined as most information coming from trials at low risk of bias, 'unclear' risk of bias as most information coming from trials at low or unclear risk of bias and 'high' risk of bias as sufficient proportion of information coming from trials at high risk of bias.
Measures of treatment effect
When there was at least two included trials for a comparison of a given outcome, we tried to express dichotomous data as odds ratio (OR) or risk ratios (RR) with 95% confidence intervals (CIs). For continuous outcomes measured on the same scale (e.g. weight loss in kilograms), we estimated the intervention effect using the mean difference (MD) with 95% CIs. For continuous outcomes measuring the same underlying concept (e.g. health‐related quality of life) but using different measurement scales, we planned to calculate the standardised mean difference (SMD) with 95% CIs. We planned to express time‐to‐event data as hazard ratios (HR) with 95% CIs.
Unit of analysis issues
We took into account the level at which randomisation occurred, such as cross‐over trials, cluster‐randomised trials and multiple observations for the same outcome. If more than one comparison from the same trial was eligible for inclusion in the same meta‐analysis, we either combined groups to create a single pair‐wise comparison, or we appropriately reduced the sample size so that the same participants did not contribute data to the meta‐analysis more than once (splitting the 'shared' group into two or more groups). Although the latter approach offers some solution for adjusting the precision of the comparison, it does not account for correlations arising from inclusion of the same set of participants being in multiple comparisons (Higgins 2011b).
We attempted to re‐analyse cluster‐RCTs that did not appropriately adjust for potential clustering of participants within clusters in their analysis. Variance of the intervention effects were inflated by a design effect. Calculation of a design effect involves estimation of an intracluster correlation coefficient (ICC). We obtained estimates of ICCs by contacting trial authors, or by imputing ICC values using either estimates from other included trials that reported ICCs or external estimates from empirical research (e.g. Bell 2013). We planned to examine the impact of clustering by performing sensitivity analyses.
Dealing with missing data
If possible, we obtained missing data from the authors of included trials. We carefully evaluated important numerical data such as screened, randomly assigned participants, as well as intention‐to‐treat, as‐treated and per‐protocol populations. We investigated attrition rates (e.g. dropouts, losses to follow‐up, withdrawals), and we critically appraised issues concerning missing data and imputation methods (e.g. last observation carried forward).
For trials in which the SD of the outcome was not available at follow‐up or we could not recreate it, we planned to standardise it using the mean of the pooled baseline SD from trials that reported this information.
When included trials did not report means and SDs for outcomes, and we did not receive requested information from trial authors, we planned to impute these values by estimating the mean and the variance from the median, range, and size of the sample (Hozo 2005).
We planned to investigate the impact of imputation on meta‐analyses by performing sensitivity analyses, and we reported for every outcome which trials had imputed SDs.
Assessment of heterogeneity
In the event of substantial clinical, methodological or statistical heterogeneity, we did not report trial results as the pooled effect estimate in a meta‐analysis.
We identified heterogeneity by visual inspection of the forest plots and by using a standard Chi² test with a significance level of α = 0.1 (Deeks 2017). In view of the low power of this test, we considered the I² statistic, which quantifies inconsistency across trials, to assess the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003).
Had we found heterogeneity, we planned to determine possible reasons for this by examining individual trial and subgroup characteristics.
Assessment of reporting biases
If we had included 10 or more trials investigating a particular outcome, we planned to use funnel plots to assess small‐trial effects. Several explanations may account for funnel plot asymmetry, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials) and publication bias (Sterne 2017). Therefore, we interpreted results carefully (Sterne 2011).
Data synthesis
We planned to undertake (or display) a meta‐analysis only if we judged participants, interventions, comparisons and outcomes to be sufficiently similar to ensure an answer that was clinically meaningful. Unless good evidence showed homogeneous effects across trials of different methodological quality, we primarily summarised low risk of bias data using a random‐effects model (Wood 2008). We interpreted random‐effects meta‐analyses with due consideration for the whole distribution of effects and presented a prediction interval (Borenstein 2017a; Borenstein 2017b; Higgins 2009). A prediction interval requires at least three trials to be calculated and specifies a predicted range for the true treatment effect in an individual trial (Riley 2011). For rare events, such as event rates below 1%, we planned to use the Peto OR method, provided there was no substantial imbalance between intervention and comparator group sizes, and intervention effects were not exceptionally large. In addition, we performed statistical analyses according to the statistical guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017).
Subgroup analysis and investigation of heterogeneity
We expected the following characteristics to introduce clinical heterogeneity, and planned to carry out the following subgroup analyses including investigation of interactions.
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Participants who reached their final adult height at the end of the trial versus those who did not reach their final height.
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Participants who received intervention or comparator for three years versus less than three years.
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Age of participants.
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Participants who received low‐dose oxandrolone (0.03 mg/kg/day) versus those who received high‐dose oxandrolone (0.06 mg/kg/day).
Sensitivity analysis
We planned to perform sensitivity analyses to explore the influence of the following factors (when applicable) on effect sizes by restricting analysis to the following.
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Published studies.
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Taking into account risk of bias, as specified in the Assessment of risk of bias in included studies section.
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Very long or large studies to establish the extent to which they dominated the results.
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Use of the following filters: diagnostic criteria, imputation, language of publication, source of funding (industry versus other) or country.
We planned to test the robustness of results by repeating analyses using different measures of effect size (i.e. RR, OR, etc.) and different statistical models (fixed‐effect and random‐effects models).
Certainty of the evidence
We presented the overall certainty of the evidence for each outcome specified below, according to the GRADE approach, which takes into account issues related to internal validity (risk of bias, inconsistency, imprecision, publication bias) and external validity (such as directness of results). Three review authors (SM, HA, YSA) independently rated the certainty of the evidence for each outcome. We resolved differences in assessment by discussion or by consultation with a fourth review author (YA).
We included an appendix entitled 'Checklist to aid consistency and reproducibility of GRADE assessments' (Appendix 15), to help with standardisation of the 'Summary of findings' table (Meader 2014). Alternatively, we planned to use GRADEpro Guideline Development Tool (GDT) software and would have presented evidence profile tables as an appendix (GRADEpro GDT). We presented results for outcomes as described in the Types of outcome measures section. If meta‐analysis was not possible, we presented the results in a narrative format in the 'Summary of findings' table. We justified all decisions to downgrade the certainty of the evidence using footnotes, and we made comments to aid the reader's understanding of the Cochrane Review when necessary.
'Summary of findings' table
We presented a summary of the evidence in a 'Summary of findings' table. This provided key information about the best estimate of the magnitude of effect, in relative terms and as absolute differences for each relevant comparison of alternative management strategies, numbers of participants and trials addressing each important outcome, and a rating of overall confidence in effect estimates for each outcome. We created the 'Summary of findings' table using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2017), along with Review Manager 5 (Review Manager 2014).
Interventions presented in the 'Summary of findings' table were oxandrolone plus GH and comparators were GH treatment only.
We reported the following outcomes, listed according to priority.
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Improvement in final adult height.
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Adverse events.
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Health‐related quality of life.
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Effects on speech.
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Effects on cognition.
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Effects on psychological status.
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All‐cause mortality.
Results
Description of studies
For a detailed description of trials, see the Characteristics of included studies, Characteristics of excluded studies, and Characteristics of ongoing studies tables.
Results of the search
The search identified 300 records. After removal of duplicates, we screened the title and abstracts of 199 records. We identified 164 of these as clearly irrelevant. The remaining 35 records underwent full‐text review (see Figure 1). We excluded five trials for the following reasons: no control group (Nilsson 1996), short follow‐up period (Ferrández 1989), and not an RCT design (Joss 1997; Sas 2014; Sheanon 2015). We included six trials (30 records) in the review (Gault 2011; Job 1991; Menke 2010; Rosenfeld 1998; Stahnke 2002; Zeger 2011).
Study flow diagram. RCT: randomised controlled trial.
Included studies
A detailed description of the characteristics of included trials is presented elsewhere (see Characteristics of included studies table; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 9; Table 1). The following is a succinct overview.
Source of data
We obtained all included trials from published literature.
Comparisons
In general, trials compared oxandrolone plus GH treatment to GH treatment alone. The dose of oxandrolone and GH treatments varied across trials, see Appendix 4.
Overview of trial populations
Trial authors randomised 498 participants, 267 participants to oxandrolone plus GH treatment and 231 participants to comparator groups. Individual trial sample size ranged from 22 to 133 participants (see Table 1).
Trial design
Five trials were multicentre (Gault 2011; Job 1991; Menke 2010; Rosenfeld 1998; Zeger 2011). The number of centres ranged from 2 to 36. Three trials were blinded for participants, personnel and outcome assessors (Gault 2011; Menke 2010; Zeger 2011). The trials were performed from 1983 to 2011. The duration of interventions ranged from 3 to 7.6 years. All six trials had a run‐in period. One trial was terminated early due to unavailability of oxandrolone because the sole European manufacturer of oxandrolone stopped production in 2004 and 2008 (Gault 2011).
Settings
Five trials were conducted in paediatric clinics or paediatric endocrinology clinics (Gault 2011; Job 1991; Menke 2010; Stahnke 2002; Zeger 2011). One trial was in medical centres (Rosenfeld 1998).
Participants
All participants were aged up to 18 years with TS. All participants came from high‐income countries. Most trials did not specify ethnic groups. The mean age of participants at start of therapy ranged from 9 to 12 years. All trials reported comorbidities, co‐interventions and comedications used by participants. Major exclusion criteria included major illnesses and previous use of hormonal treatments (see Appendix 5; Appendix 6).
Diagnosis
All trials include females with TS, with specific referral to diagnosis criteria.
Interventions
None of the trials reported treatment before enrolment. The intervention (oxandrolone) was given as oral medication. The total dose for oxandrolone ranged from a daily dose of 0.03 mg/kg to 0.125 mg/kg (0.125 mg/kg (Rosenfeld 1998), 0.1 mg/kg (Stahnke 2002), 0.06 mg/kg (Job 1991; Menke 2010; Zeger 2011), 0.05 mg/kg (Gault 2011; Stahnke 2002), 0.03 mg/kg (Menke 2010)).
Duration of treatment ranged from 3 to 13 years. All trials used interventions and comparators (two trials used two comparator arms which we did not include in the final analysis; Rosenfeld 1998; Stahnke 2002; Appendix 4).
Outcomes
Two trials explicitly stated primary and secondary outcomes in the publication (Gault 2011; Menke 2010). Three trials had information in trial registers (Gault 2011; Menke 2010; Zeger 2011), and one trial published a paper on the design of the study (Stahnke 2002) (see Appendix 7). Where available, there were no major differences between defined primary outcomes in the publication and trial registers. All trials collected a median of one (one to six) outcomes. Five trials reported adverse events (Gault 2011; Menke 2010; Rosenfeld 1998; Stahnke 2002; Zeger 2011). Only one trial investigated health‐related quality of life (Menke 2010). The included trials had variable definitions of our primary outcome measurement improvement in final adult height (see Appendix 9).
Excluded studies
We excluded five trials that did not fulfil our inclusion criteria. One trial had no comparator group (Nilsson 1996), one had a short follow‐up period (six months only; Ferrández 1989), and three trials were not RCTs (Joss 1997; Sas 2014; Sheanon 2015). A short description of the excluded trials can be found in the Characteristics of excluded studies table.
Risk of bias in included studies
For details on the risk of bias of the included trials, see the Characteristics of included studies table.
For an overview of review authors' judgements about each risk of bias item for individual trials and across all trials, see Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the study did not measure that particular outcome).
Allocation
Two trials reported adequately on random sequence generation and allocation concealment (low risk of bias; Gault 2011; Menke 2010). The remaining trials were at unclear risk of selection bias.
Blinding
Three trials were double‐blinded for participants and personnel and blinded on all reported outcomes for outcome assessors (Gault 2011; Menke 2010; Zeger 2011). Three trials had no sufficient information on blinding procedures (unclear risk; Job 1991; Rosenfeld 1998; Stahnke 2002). We judged two trials at high risk of performance bias and detection bias for the outcome adverse events (Rosenfeld 1998; Stahnke 2002).
Incomplete outcome data
Three trials (Job 1991; Menke 2010; Zeger 2011) performed an ITT analysis (low risk of bias). We judged one trial at high risk of attrition bias for the outcome measures adverse events and improvement in final height/increase in height velocity (Stahnke 2002).
Selective reporting
Four trials were at low risk of reporting bias (Gault 2011; Menke 2010; Rosenfeld 1998; Zeger 2011). Two trials were at high risk of reporting bias.
Other potential sources of bias
Five trials were at low risk of bias (Gault 2011; Job 1991; Menke 2010; Rosenfeld 1998; Zeger 2011). One trial was at high risk if other bias because participants were switched between groups to create a third new group after randomisation that could have negatively affected the randomisation process (Stahnke 2002).
Effects of interventions
Baseline characteristics
For details of baseline characteristics, see Appendix 5 and Appendix 6.
Oxandrolone plus growth hormone versus growth hormone only
Primary outcomes
Improvement in final adult height
Oxandrolone plus GH compared with GH only showed an improvement in final height (MD 2.7 cm, 95% CI 1.3 to 4.1; P < 0.001; 5 trials, 270 participants; Analysis 1.1; moderate‐quality evidence). The 95% prediction interval ranged between 0.3 cm and 5.1 cm.
Several additional analyses did not change this result substantially (e.g. excluding low‐quality trials, Analysis 1.2, and the subgroup of participants who reached final adult height by excluding trials measuring near adult height and predicted height, Analysis 1.3). For illustrative purposes, we provided supplementary data with very limited amount of information reporting various height measures and usually consisting of one trial only (Analysis 1.4; Analysis 1.5; Analysis 1.6; Analysis 1.7; Analysis 1.8; Analysis 1.9; Analysis 1.10; Analysis 1.11; Analysis 1.12; Analysis 1.13; Analysis 1.14; Analysis 1.15; Analysis 1.16; Analysis 1.17; Analysis 1.18; Analysis 1.19; Analysis 1.20; Analysis 1.21; Analysis 1.22). Data on adult height could not be used from one trial because authors did not provide SDs (Zeger 2011).
Health‐related quality of life
One trial investigated health‐related quality of life (Menke 2010).
The follow‐up study of Menke 2010, where only 68 women (133 children and adolescents were initially randomised) participated in the double‐blinded follow‐up, with a mean age of 24 years and mean time since stopping oxandrolone plus GH of 8.7 years, reported health‐related quality of life using three questionnaires (Beck Depression Inventory – Second Edition Netherlands (BDI‐II‐NL); Symptom Checklist‐90‐revised (SCL‐90‐R); SF‐36). The comparison of oxandrolone plus GH versus GH only in 46 participants for total and mean scores showed inconclusive results (Analysis 1.23; Analysis 1.24; Analysis 1.25).
Adverse events
The random‐effects RR for adverse events comparing oxandrolone plus GH with GH only was 3.27 (95% CI 0.75 to 14.22; P = 0.11; 4 trials, 283 participants; Analysis 1.26). Thirty‐five out of 162 (21.6%) participants receiving oxandrolone plus GH compared with 8/121 (6.6%) participants receiving GH only reported adverse events. Fixed‐effect meta‐analysis showed a RR of 3.43 (95% CI 1.64 to 7.17). Evidence‐synthesis in the case of very few trials is difficult (Bender 2018). Elimination of the trials with high or unclear risk of performance bias, detection bias and attrition bias for the outcome measure adverse events (Rosenfeld 1998; Stahnke 2002) resulted in a RR of 1.81 (95% CI 0.83 to 3.96; P = 0.42; 2 trials, 170 participants; low‐quality evidence). In the remaining two trials, 16/86 (18.6%) participants receiving oxandrolone plus GH compared with 8/84 (9.5%) participants receiving GH only reported adverse events (Menke 2010; Zeger 2011). Adverse events comprised signs of virilisation (e.g. deepening of the voice, hirsutism), hypothyroidism, impaired glucose tolerance and increased liver enzymes. For full details, see Appendix 10; Appendix 11; Appendix 12.
Secondary outcomes
Increase in height velocity
Oxandrolone plus GH compared with GH only for height velocity showed different results depending on whether a random‐effects model or fixed effect model was used. Trials used several methods to report the increment in height per year (Analysis 1.27; Analysis 1.28; Analysis 1.29; Analysis 1.30; Analysis 1.31; Analysis 1.32; Analysis 1.33; Analysis 1.34; Analysis 1.35). Taking into account the small number of trials and most effect estimates pointing in the same direction, we used a qualitative evidence synthesis approach (Bender 2018).
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Two trials (59 participants) measured height velocity at one year and showed an MD in favour of oxandrolone plus GH of 1.8 cm and 3.8 cm (Analysis 1.27).
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Three trials (98 participants) measured height velocity at two years and showed an MD in favour of oxandrolone plus GH of 0.3 cm, 1.5 cm and 1.9 cm (Analysis 1.29).
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Two trials (57 participants) measured height velocity at three years and showed an MD in favour of oxandrolone plus GH of 0.7 cm and 2.1 cm (Analysis 1.32).
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Two trials (107 participants) measured height velocity at four years and showed a disadvantage and advantage of oxandrolone plus GH of –0.2 cm and 4 cm (Analysis 1.34).
All‐cause mortality
None of the trials reported all‐cause mortality.
Bone maturation
Oxandrolone plus GH compared with GH only showed an MD for bone age of 0.16 years (95% CI –0.46 to 0.78; P = 0.23; 3 trials, 91 participants; Analysis 1.36).
Effects on cognition
Zeger 2011 reported summary scores for working memory, spatial cognition, executive function and verbal abilities using the Wechsler Intelligence Scale for Children‐Revised (WISC‐R). After two years, comparison of oxandrolone plus GH versus GH only in 51 participants showed inconclusive results (very low‐quality evidence; Analysis 1.37).
Effects on psychological status
One trial in 106 participants investigated psychological and behavioural characteristics using the Child Behavior Checklist (CBCL), the Junior Dutch Personality Questionnaire (DPQ‐J), the state‐subscale of the Spielberger's State‐Trait Anger Scale, the Romantic and Sexual Interest Questionnaire, the Mood Questionnaire and the Gender Role Questionnaire (Menke 2010). There were no evident psychological virilising effects in the areas of behaviour, aggression, romantic and sexual interest, mood and gender role (very low‐quality evidence).
Effects on speech
One trial including 88 participants assessed whether oxandrolone treatment caused voice deepening (Menke 2010). GH‐treated girls had relatively high‐pitched voices. Oxandrolone plus GH decreased voice frequency in a dose‐dependent way. Most voice frequencies remained within the normal range, but became occasionally lower, especially with oxandrolone plus GH 0.06 mg/kg/day treatment. Results were inconclusive for oxandrolone plus GH 0.03 mg/kg/day (very low‐quality evidence).
Socioeconomic effects
None of the trials reported on details of socioeconomic effects. However, one trial comparing oxandrolone plus GH with GH plus placebo reported costs of treatment (Menke 2010). Trial authors stated: "When corrected for bone age at starting GH, the duration of GH therapy was shorter on GH+Ox [growth hormone plus oxandrolone] 0.03 and 0.06 (–0.4 yr [years] and –0.8 yr, P = 0.06 and P = 0.001, respectively), and the cumulative costs of GH were lower (–10,100 ± 6,100 and –13,500 ± 6,300 euro, P = 0.1 and P = 0.03, respectively) than on GH+Pl [growth hormone plus placebo] (mean cumulative costs, 161,200 ± 59,500 euro)".
Subgroup analyses
With the exception of the subgroup of participants who reached final adult height by excluding trials measuring near adult height and predicted height, we did not perform subgroups analyses because there were not enough trials.
Sensitivity analyses
With the exception of low‐quality versus high‐quality trials, we did not perform sensitivity analyses because there were not enough trials.
Assessment of reporting bias
We did not draw funnel plots due to limited number of trials.
Ongoing trials
We found no ongoing trials. All trials registered in different phases were completed and published.
Discussion
Summary of main results
This Cochrane systematic review intended to examine the effects of oxandrolone therapy on different outcomes in girls with TS. Six RCTs met our inclusion criteria and all provided data. All trials compared a combination of oxandrolone and GH, at different dosing regimens, to GH alone or combined with placebo. The intervention period lasted from 3 to 7.6 years. Trials were carried out from 1983 to 2011 and enrolled 498 participants from fairly comparable patient populations.
The findings of our review led to the following main conclusions: overall, oxandrolone had a positive effect on adult height, height gain and height velocity when used in combination with GH. There were numerically more adverse events reported in the oxandrolone treatment arms. However, results did not clearly show an advantage or disadvantage of the intervention or comparator group, which may be caused by including only two trials and a small number of participants with events.
Overall completeness and applicability of evidence
This review provides the most up‐to‐date assessment of the efficacy and safety of the combination therapy of oxandrolone and GH on adult height in girls with TS. The six included trials used a combination of oxandrolone and GH, no trial used oxandrolone alone for the whole intervention period. All trials compared the combination therapy to GH alone.
This review provides reliable information about the impact of oxandrolone in combination with GH on a range of adult height outcomes. Adult height was the most commonly reported outcome among the included trials. Other commonly reported outcomes were adult height gain, height velocity, bone maturation and overall presence of adverse events. Limited evidence due to small number of studies was available for the outcomes bone maturation, socioeconomic effects, cognition, psychological status and speech. No trial reported all‐cause mortality or health‐related quality of life (one follow‐up study with less than 50% of initially randomised participants showed inconclusive results comparing oxandrolone plus GH for total and mean scores in three different questionnaires).
Quality of the evidence
We assessed the certainty of the evidence for our prespecified outcomes using the GRADE approach (Appendix 15). Most trials did not report study methodology in adequate detail. For example, we judged that only two trials sufficiently reported both allocation concealment and random sequence generation (Gault 2011; Menke 2010). Contact with trial authors did not provide any additional information.
The major reason for downgrading the level of certainty of the evidence was imprecision due to the low number of trials, low number of participants or both.
Potential biases in the review process
We followed the Cochrane search strategy which includes searching trials registers as well as handsearching any relevant articles or review papers. Therefore, we believe it is unlikely that we missed relevant trials. However, there is a possibility that we did not detect unpublished data. Due to the small number of trials and limited amount of data, we could only perform very limited subgroup and sensitivity analyses. The doses used for the interventions and comparisons varied across trials and we were unable to analyse each dose regimen separately due to the limited number of trials. In addition, treatment durations and follow‐up periods varied across trials. There was incomplete outcome reporting in some trials. Although we attempted to locate all relevant data, we were unable to reach the original trials investigators due to incomplete correspondence with trial investigators.
Agreements and disagreements with other studies or reviews
Our review and meta‐analysis supports the conclusion of three recent reviews. The review published by Sheanon and Backeljauw (Sheanon 2015), included four published, randomised, placebo‐controlled, double‐blinded trials. The four mentioned trials were also included in our meta‐analysis and they revealed that adding oxandrolone to GH‐treated girls with TS can result in an increase in height velocity and lead to a mild increase in their adult heights. The review published by Li, Cheng and Xiu (Li 2018) included 10 published, randomised trials (10 trials and 11 records; Davenport 2007; Gault 2011; Job 1991; Menke 2010; Quigley 2002; Rosenfeld 1986; Rosenfeld 1998; Ross 2011; Stahnke 2002; Stephure 2005; Zeger 2011). We excluded some of these records as they were out of the scope of our review, and included the remainder. Li and colleagues concluded that adding oxandrolone to the therapy of GH‐treated girls with TS resulted in an increase in height velocity and led to a mild increase in their adult heights by 2.46 cm (Li 2018). Another narrative review was published by a group of authors investigating RCTs addressing the effects of oxandrolone in GH‐treated girls with TS (Sas 2014). This review found that addition of oxandrolone increased the final adult height by 2.3 cm to 4.6 cm. Gault and colleagues published a conference abstract in 2015 (Gault 2015), which updated the interim analysis of the 2011 paper (Gault 2011), and added 20 participants with data that could not be included in our meta‐analysis as there were no comparison groups and different outcomes (i.e. delayed pubertal induction) (Beller 2013).
Study flow diagram. RCT: randomised controlled trial.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the study did not measure that particular outcome).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 1 Final adult height.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 2 Final adult height: excluding low‐quality trials.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 3 Final adult height: trials reporting strictly adult height (excluding trials measuring near adult height and predicted height).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 4 Final adult height: trials reporting strictly adult height (excluding low‐quality trials).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 5 Final height/near adult height reported.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 6 Predictable adult height.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 7 Maximum height.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 8 Adult height gain.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 9 Final adult height SDS (Turner reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 10 Final adult height SDS (healthy reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 11 Final adult height delta height SDS (Turner reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 12 Final adult height delta height SDS (healthy reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 13 Final adult height minus predicted adult height (height gain).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 14 Difference in height gain vs placebo (final height – placebo final height).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 15 Near adult height.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 16 Near adult height SDS (Turner reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 17 Near adult height SDS (healthy reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 18 Near adult height delta height SDS (Turner reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 19 Near adult height delta height SDS (healthy reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 20 Increase in near adult height from baseline.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 21 Near adult height minus predicted adult height.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 22 Difference in height gain over placebo (near adult height – placebo final height).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 23 Health‐related quality of life (BDI‐II‐NL).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 24 Health‐related quality of life (SCL‐90‐R).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 25 Health‐related quality of life (SF‐36).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 26 Adverse events.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 27 Height growth (velocity) year 1.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 28 Height growth (velocity) SDS year 1 (Turner reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 29 Height velocity year 2.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 30 Height velocity, SDS year 2 (Turner reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 31 Height velocity, SDS year 2 (healthy reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 32 Height velocity year 3.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 33 Height velocity SDS year 3 (Turner reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 34 Height velocity year 4.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 35 Height velocity SDS year 4 (Turner reference).
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 36 Bone maturation, bone age in years.
Comparison 1 Oxandrolone plus growth hormone (GH) versus GH only, Outcome 37 Effect on cognition at year 2.
| Oxandrolone for growth hormone‐treated girls aged up to 18 yearswith Turner syndrome | ||||||
| Patient: girls aged up to 18 years with Turner syndrome Settings: mostly paediatric endocrine centres Intervention: oxandrolone + growth hormone Comparison: growth hormone alone | ||||||
| Outcomes | Growth hormone | Oxandrolone + growth hormone | Relative effect | No of participants | Certainty of the evidence | Comments |
| Improvement in final adult height (cm) Follow‐up: 3–10 years | The mean final adult height ranged across control groups from 149.6 cm to 155.6 cm | The mean final adult height in the intervention groups was 2.7 cm higher (1.3 cm higher to 4.1 cm higher) | — | 270 (5) | ⊕⊕⊕⊝ | 95% prediction interval 0.3–5.1 cm |
| Adverse events (N) Follow‐up: 3–10 years | 95 per 1000 | 172 per 1000 (79 to 377) | RR 1.81 (0.83 to 3.96) | 170 (2) | ⊕⊕⊝⊝ | Data based on 2/4 trials with overall low risk of bias for adverse events. |
| Health‐related quality of life | Not reported | Follow‐up study with < 50% of initially randomised participants showed inconclusive results comparing oxandrolone + GH for total and mean scores (3 questionnaires). | ||||
| Effects on speech (voice frequency) Follow‐up: 6 years | See comment | 88 (1) | ⊕⊝⊝⊝ | Most voice frequencies remained within the normal range, but became occasionally lower, especially with oxandrolone + GH 0.06 mg/kg/day; results were inconclusive for oxandrolone + GH 0.03 mg/kg/day. | ||
| Effects on cognition Follow‐up: 2 years | See comment | 51 (1) | ⊕⊝⊝⊝ | Summary scores for working memory, spatial cognition, executive function and verbal abilities using the WISC‐R; after 2 years, comparison of oxandrolone + GH vs GH showed inconclusive results. | ||
| Effects on psychological status Follow‐up: 6 years | See comment | 106 (1) | ⊕⊝⊝⊝ | There were no evident psychological virilising effects in the area of behaviour, aggression, romantic and sexual interest, mood and gender role. | ||
| All‐cause mortality | Not reported | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level because of imprecision (low median sample size) – for details, see Appendix 15. | ||||||
| Study ID | Intervention(s) and comparator(s) | Description of power and sample size calculation | Screened/eligible | Randomised | Analysed | Finishing trial | Randomised finishing trial | Follow‐up |
| (parallel RCT) | I: oxandrolone + GH | Sample size was estimated for height velocity: 60 girls (30 per group) yielded a > 95% probability to detect a statistically significant difference in height velocity between the GH + oxandrolone and GH + placebo groups at year 2. 70 girls completed the initial 2 years, thereafter 35 girls receiving oxandrolone and 31 girls receiving placebo chose to continue in the 2‐year double‐blind extension study (47 girls completed this phase and were evaluated at the end of year 4). | NR/76 | 40 | 37 | 37 (24 extension period) | 93 (60 extension period) | 2 years (2 years) |
| C: GH + placebo | 36 | 33 | 33 (23 extension period) | 92 (64 extension period) | ||||
| Total: | 76 | 70 | 70 (47 extension period) | 92 (62 extension period) | ||||
| (parallel factorial RCT) | I: oxandrolone + GH | Assuming an SD of 5 cm, 50 girls were needed in each group to detect a difference between groups in mean final height (defined as height velocity < 1 cm/year and bone age ≥ 15.5 years) of 2.8 cm with 80% power at 5% significance; total of 100 participants. | NR/106 | 51 | NA | NA | NA | Unclear (15 years) |
| C: GH + placebo | 55 | NA | NA | NA | ||||
| Total: | 106 | NA | NA | NA | ||||
| (parallel RCT) | I1: oxandrolone 0.03 mg/kg/day + GH | 15 girls per dosage and age group were needed to achieve a power of 80% to detect a difference (P = 0.05, 2 sided) in first‐year height velocity of 2 cm with an assumed SD of 2.6. ITT analyses were performed and differences in adult height gain were also assessed by a PP analysis. | NR/184 | 46 | 42 (ITT) | NA | NA | 1 year (2 years) |
| I2: oxandrolone 0.06 mg/kg/day + GH | 39 | 36 (ITT) | NA | NA | ||||
| C: GH + placebo | 48 | 42 (ITT) | NA | NA | ||||
| Total: | 133 | 120 (ITT) | NA | NA | ||||
| (parallel RCT) | I1: oxandrolone + GH | — | NR/91 | 44 (33) | NA | NA | NA | Initial phase: 12 months (2 years; 4 years; 5 years) |
| I2: transient oxandrolone + GH | 0 (38) | NA | NA | NA | ||||
| C: GH | 47 (20) | NA | NA | NA | ||||
| Total: | 91 (53) | NA | NA | NA | ||||
| (parallel RCT/CCT after 1–2 years) | I1: oxandrolone | — | NR/70e | 18 | NA | NA | NA | 12–24 months (3–6 years) |
| I2: oxandrolone + GH | 17 | |||||||
| C1: GH | 17 | |||||||
| C2: no treatment | 18 | |||||||
| total: | 70 | NA | NA | NA | ||||
| (parallel RCT) | I: oxandrolone + GH | — | NR/22 | 12 | 12 | 12 | 100 | 3 years |
| C: GH | 10 | 10 | 10 | 100 | ||||
| Total: | 22 | 22 | 22 | 100 | ||||
| Overall total | All interventions All comparators All interventions and comparators | 267 | — | |||||
| 231 | ||||||||
| 498 | ||||||||
| aFollow‐up under randomised conditions until end of trial (= duration of intervention + follow‐up postintervention or identical to duration of intervention); extended follow‐up refers to follow‐up of participants once the original trial was terminated as specified in the power calculation. C: comparator; CCT: controlled clinical trial; GH: growth hormone; I: intervention; ITT: intention‐to‐treat; N: number; NA: not applicable; NR: not reported; PP: per protocol; RCT: randomised controlled trial; SD: standard deviation. | ||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Final adult height Show forest plot | 5 | 270 | Mean Difference (IV, Random, 95% CI) | 2.71 [1.32, 4.11] |
| 2 Final adult height: excluding low‐quality trials Show forest plot | 3 | 229 | Mean Difference (IV, Random, 95% CI) | 2.87 [‐0.56, 6.30] |
| 3 Final adult height: trials reporting strictly adult height (excluding trials measuring near adult height and predicted height) Show forest plot | 3 | 226 | Mean Difference (IV, Random, 95% CI) | 2.54 [0.31, 4.78] |
| 4 Final adult height: trials reporting strictly adult height (excluding low‐quality trials) Show forest plot | 2 | 166 | Mean Difference (IV, Random, 95% CI) | 2.87 [‐0.56, 6.30] |
| 5 Final height/near adult height reported Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 6 Predictable adult height Show forest plot | 2 | 44 | Mean Difference (IV, Random, 95% CI) | 0.29 [‐2.78, 3.36] |
| 7 Maximum height Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 8 Adult height gain Show forest plot | 4 | 246 | Mean Difference (IV, Random, 95% CI) | 3.15 [1.93, 4.37] |
| 9 Final adult height SDS (Turner reference) Show forest plot | 2 | 106 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.31, 0.51] |
| 10 Final adult height SDS (healthy reference) Show forest plot | 2 | 166 | Mean Difference (IV, Random, 95% CI) | ‐0.30 [‐1.28, 0.68] |
| 11 Final adult height delta height SDS (Turner reference) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 12 Final adult height delta height SDS (healthy reference) Show forest plot | 2 | 166 | Mean Difference (IV, Random, 95% CI) | 0.54 [0.24, 0.83] |
| 13 Final adult height minus predicted adult height (height gain) Show forest plot | 2 | 106 | Mean Difference (IV, Random, 95% CI) | 3.04 [1.15, 4.94] |
| 14 Difference in height gain vs placebo (final height – placebo final height) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 15 Near adult height Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 16 Near adult height SDS (Turner reference) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 17 Near adult height SDS (healthy reference) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 18 Near adult height delta height SDS (Turner reference) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 19 Near adult height delta height SDS (healthy reference) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 20 Increase in near adult height from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 21 Near adult height minus predicted adult height Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 22 Difference in height gain over placebo (near adult height – placebo final height) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 23 Health‐related quality of life (BDI‐II‐NL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 24 Health‐related quality of life (SCL‐90‐R) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 25 Health‐related quality of life (SF‐36) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 26 Adverse events Show forest plot | 4 | 283 | Risk Ratio (M‐H, Random, 95% CI) | 3.27 [0.75, 14.22] |
| 27 Height growth (velocity) year 1 Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 28 Height growth (velocity) SDS year 1 (Turner reference) Show forest plot | 2 | 58 | Mean Difference (IV, Random, 95% CI) | 1.52 [0.72, 2.33] |
| 29 Height velocity year 2 Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 30 Height velocity, SDS year 2 (Turner reference) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 31 Height velocity, SDS year 2 (healthy reference) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 32 Height velocity year 3 Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 33 Height velocity SDS year 3 (Turner reference) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 34 Height velocity year 4 Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 35 Height velocity SDS year 4 (Turner reference) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 36 Bone maturation, bone age in years Show forest plot | 3 | 91 | Mean Difference (IV, Random, 95% CI) | 0.16 [‐0.46, 0.78] |
| 37 Effect on cognition at year 2 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 37.1 Working memory | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 37.2 Spatial cognition | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 37.3 Executive function | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 37.4 Verbal abilities | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
