Twenty years ago it was believed that pubertal growth was stimulated by testicular
androgen in boys and by adrenal
androgen in girls.
Estrogen, which was used to inhibit growth in excessively tall girls, was not thought to have growth-promoting effects. We hypothesized that
estrogen has a biphasic effect on epiphyseal growth, with maximal stimulation at low levels. We showed that the administration of low doses of
estrogen, corresponding to a serum
estradiol level of about 4 pg/ml (15 pmol/l) caused more than a 60% increase over the prepubertal growth rate in both boys and girls. To test the hypothesis that
estrogen is the principal mediator of the pubertal growth spurt in boys, we administered the
aromatase inhibitor,
testolactone, to boys with
familial male-limited precocious puberty.
Testolactone produced near normalization of both growth velocity and bone maturation, despite levels of serum
testosterone that remained within the adult male range. The observation that low levels of
estrogen stimulate growth and bone maturation suggested that
estrogen might explain the more rapid epiphyseal maturation of prepubertal girls compared to boys. To determine whether prepubertal girls have higher
estrogen levels than prepubertal boys, we developed an ultrasensitive recombinant cell bioassay for
estrogen with a sensitivity of 0.02 pg/ml (0.07 pmol/l)
estradiol equivalents. Prepubertal girls had approximately eight-fold higher levels of serum
estradiol than did prepubertal boys (0.6 +/- 0.6 pg/ml (SD) (2.2 +/- 2.2 pmol/l) vs 0.08 +/- 0.2 pg/ml (0.29 +/- 0.73 pmol/l), P < 0.05). We concluded that the pubertal growth spurt of both sexes is driven primarily by
estrogen, and that the more rapid epiphyseal maturation of prepubertal girls (vs boys) may be explained by their higher
estradiol levels.