Estrogens have been shown to rapidly inhibit longitudinal growth in tall boys. To antagonize the initial growth accelerating effect of T, 41 boys with an initial height prediction in excess of 203 cm were treated prospectively with either T enanthate (TE) 250 mg/wk im in combination with ethinylestradiol (EE2) 0.1 mg/d taken orally for the first 5.8 +/- 0.47 wk (mean +/- SE) of treatment (group 1, n = 20) or with TE alone (group 2, n = 21). Patients were randomized to one or the other treatment regimen. Mean (+/-SE) predicted adult height was 206.8 +/- 0.7 cm in group 1 and 206.4 +/- 0.8 cm in group 2. Total duration of treatment was 16.1 +/- 0.8 months and 14.0 +/- 1.2 months in group 1 and 2, respectively (NS). EE2-induced side effects in group 1 (gynecomastia) were limited and fully reversible. No negative long-term sequelae were found at final height with respect to hypothalamic-pituitary-gonadal axis activity and to testis volumes. Although there was a tendency to a lower initial growth velocity measured by knemometry in group 1 (0.30 +/- 0.05 vs. 0.38 +/- 0.05 mm/wk, NS), final height did not differ in both study groups (195.0 +/- 0.8 cm in group 1, 194.6 +/- 0.8 cm in group 2). Similarly, height reduction (initial predicted adult height minus final height) was not significantly different between the two groups (12.0 +/- 0.9 cm in group 1, 11.7 +/- 0.9 cm in group 2). In conclusion, the addition of EE2 during the initial treatment phase to high-dose T in tall boys has no significant effect on height reduction. The results of this clinical trial suggest that the initial growth inhibiting effect of EE2 on the epiphyseal growth plates is overridden by the long-term administration of high dose TE.