Use of aromatase inhibitors to increase final height.

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.