Effect of Oxandrolone and Timing of Oral Ethinylestradiol Initiation on Pubertal Progression, Height Velocity and Bone Maturation in the UK Turner Study

Abstract

Background: A UK study showed final height in Turner syndrome (TS) girls receiving growth hormone is affected by age at pubertal induction and oxandrolone (Ox). Using data from that study, we analysed the effect of timing of oral ethinylestradiol (EE₂) and Ox on height velocity (HV), bone maturation and pubertal progression, and compared growth response in EE₂-treated versus spontaneous puberty. Methods: Analysis of HV, bone age and pubertal stage in 92 TS girls (7-13 years) randomised to Ox (0.05 mg/kg/day; max: 2.5 mg/day) or placebo from 9 years, and EE₂ (year 1: 2 µg/day; year 2: 4 µg/day; year 3: 6/8/10 µg/day × 4 months) or placebo at 12 years with EE₂ at 14 years. Girls enrolled at >12.25 years received EE₂ at 14 years (‘late group'). Results: Fifty-six girls were randomised to EE₂ at 12 years (n = 28, 11 Ox) or 14 years (n = 28, 13 Ox); there were 19 girls in the late group (9 Ox) and 17 girls with spontaneous puberty (10 Ox). Girls receiving EE₂ at 12 versus 14 years had faster bone maturation, but neither group showed acceleration. Ox increased HV without altering bone maturation or pubertal progression. Girls with spontaneous puberty had greater pubertal growth (mean PHV 8.5 cm/year; p < 0.001) and height gain (p < 0.001) than EE₂-treated girls despite similar mean enrolment height SD and dysmorphology scores. Conclusion: Pubertal induction with EE₂ does not replicate the acceleration observed in unaffected girls or TS girls with spontaneous puberty.

Estrogens and Androgens in Skeletal Physiology and Pathophysiology

“…Short courses of low-dose T or the weak, nonaromatizable androgen oxandrolone have been used in boys with CDGP to accelerate puberty and height velocity, without adversely affecting age/epiphyseal closure or ultimate height (107,417). Likewise, oxandrolone treatment of girls with Turner syndrome receiving GH increases ultimate height by accelerating height velocity, without altering bone maturation or pubertal progression (167,409,434). The mechanism by which nonaromatizable androgens accelerate growth in the face of supraphysiological GH treatment remains unexplained, but an increase in IGF-I due to androgen modulation of GH patterns remains a possibility (112,409).…”

“…Likewise, oxandrolone treatment of girls with Turner syndrome receiving GH increases ultimate height by accelerating height velocity, without altering bone maturation or pubertal progression (167,409,434). The mechanism by which nonaromatizable androgens accelerate growth in the face of supraphysiological GH treatment remains unexplained, but an increase in IGF-I due to androgen modulation of GH patterns remains a possibility (112,409). (165,172,382).…”

Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations

“…Low-dose estrogen regimens do not appear to interfere with growth response to GH therapy when begun at 11 to 12 years of age at low doses (21,24,26,49). Ultra-low dose oral EE (starting at 25 ng/kg/d at ages 5 to 12 years) in childhood TS has been reported but is not currently recommended, based on an increased risk of earlier thelarche and no proven benefit to growth or pubertal outcome (25).…”