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  • Review Article
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Aromatase inhibitors in pediatrics

Nature Reviews Endocrinology volume 8, pages 135–147 (2012)Cite this article

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Abstract

Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole—currently approved as adjuvant therapy for breast cancer—have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz–Jeghers syndrome, McCune–Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz–Jeghers and McCune–Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution.

Key Points

  • Aromatase is expressed in many tissues and converts androgens to estrogens in a tissue-specific fashion

  • The third-generation aromatase inhibitors anastrozole and letrozole suppress estrogen production by 97–99% and are highly selective

  • Animal experiments have shown that the role of estrogen in growth regulation is different from that in humans, but have highlighted possible adverse effects of aromatase inhibitor use

  • Contrary to theoretical expectations, aromatase inhibitors appear ineffective in the treatment of pubertal gynecomastia

  • Evidence from controlled and uncontrolled studies in boys with short stature and/or pubertal delay suggests a positive effect of aromatase inhibitors on adult height, but more follow-up data are needed

  • The use of aromatase inhibitors in prepubertal boys is not advised because of an association with vertebral deformities

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Authors and Affiliations

  1. Department of Pediatrics, J6S, Leiden University Medical Center, Albinusdreef 2, 2333ZA, P. O. Box 9600, Leiden, 2300RC, The Netherlands

    Jan M. Wit

  2. Children's Hospital, Helsinki University Central Hospital, Stenbäckinkatu 11, P. O. Box 281, Helsinki, 00029, Finland

    Matti Hero

  3. Section of Pediatric Endocrinology, Dell Children's Medical Center of Central Texas, 4900 Mueller Boulevard, Austin, 78723, TX, USA

    Susan B. Nunez

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  1. Jan M. Wit
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Wit, J., Hero, M. & Nunez, S. Aromatase inhibitors in pediatrics. Nat Rev Endocrinol 8, 135–147 (2012). https://doi.org/10.1038/nrendo.2011.161

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