During puberty in both sexes, the mechanism involved in epiphyseal fusion is mediated by the action of
estrogen through a cascade of events including proliferation, differentiation, and apoptosis of chondrocytes. The
enzyme P450 aromatase catalyzes the aromatization of C19
androgens (
androstenedione and
testosterone) to C18
estrogens (
estrone and
estradiol). Inhibition of
estrogen action by
aromatase inhibitors (AIs) appears to decelerate the process of growth plate fusion, and thus AIs may be used therapeutically to increase adult height. The clinical experience with AIs in the pediatric setting is limited to
testolactone,
fadrozole,
letrozole, and
anastrozole.
Testolactone, a nonselective steroidal AI, has been used successfully as an adjunct to
antiandrogen and
gonadotropin-releasing hormone analogue (GnRHa),
therapy for children with
familial male-limited precocious puberty (
FMPP) and
congenital adrenal hyperplasia (CAH), and with some success in girls with
McCune-Albright syndrome. The limitations of
testolactone include its relatively low potency and the need for frequent dosing. Results of a randomized placebo-controlled trial in boys with
delayed puberty treated with
letrozole, a selective nonsteroidal AI, found that boys treated with
letrozole +
testosterone experienced delayed bone maturation and good growth response and achieved an increase in predicted adult height. In this study, only minor differences in bone density were seen between the placebo and
letrozole treatment groups, both of which were receiving concomitant
testosterone therapy. No adverse effects on testis size or
inhibin B concentration were noted. The therapeutic value of AIs in growth promotion now remains to be substantiated in future controlled clinical trials.