Use of aromatase inhibitors for height improvement in boys: a literature review

Authors

DOI:

https://doi.org/10.33448/rsd-v12i2.40181

Keywords:

Aromatase inhibitors; Growth disorders; Growth.

Abstract

Introduction: Short stature is currently one of the most common reasons for seeking and referring patients to pediatric endocrinology. Such a demand occurs not only due to the physiological factors, but also the psychological ones involved. Objective: to analyze the specific literature on aromatase inhibitors and their use in children. Method: A narrative literature review was carried out using Pubmed, Google Scholar and UptoDate databases. For the search, the following descriptors were used: “aromatase inhibitor”, “children” and “growth”. Articles on the use of aromatase inhibitors in boys with short stature were selected. Articles that focused on the use of aromatase inhibitors in cancer, the use of aromatase inhibitors exclusively in McCune Albright Syndrome and that were not located in full were excluded. A total of 1028 scientific productions were found, of which 59 met the pre-established criteria. Results and Discussion: The aromatase enzyme is a cytochrome P450 enzyme and converts androgenic precursors into estrogenic precursors. Aromatase inhibitors delay growth cartilage senescence and may be indicated in boys with current short stature with psychosocial repercussions or inadequate prediction of final height. According to previously published studies, aromatase inhibitors have been shown to be effective in the treatment of short stature. It is concluded that aromatase inhibitor treatment effectively delays bone maturation and improves adult height.

References

Bajpai, A., Simm, P. J., McPherson, S. J., Russo, V. C., Azar, W. J., Wark, J. D., Risbridger, G. P., & Werther, G. A. (2010). Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia. The Journal of endocrinology, 207(1), 27–34. https://doi.org/10.1677/JOE-10-0006

Berry J. (2005). Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer. Clinical therapeutics, 27(11), 1671–1684. https://doi.org/10.1016/j.clinthera.2005.11.013

BIG 1-98 Collaborative Group, Mouridsen, H., Giobbie-Hurder, A., Goldhirsch, A., Thürlimann, B., Paridaens, R., Smith, I., Mauriac, L., Forbes, J., Price, K. N., Regan, M. M., Gelber, R. D., & Coates, A. S. (2009). Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. The New England journal of medicine, 361(8), 766–776. https://doi.org/10.1056/NEJMoa0810818

Boeddinghaus, I. M., & Dowsett, M. (2001). Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors. The Journal of steroid biochemistry and molecular biology, 79(1-5), 85–91. https://doi.org/10.1016/s0960-0760(01)00126-1

Burnett-Bowie, S. A., McKay, E. A., Lee, H., & Leder, B. Z. (2009). Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. The Journal of clinical endocrinology and metabolism, 94(12), 4785–4792. https://doi.org/10.1210/jc.2009-0739

Buzdar, A. U., Robertson, J. F., Eiermann, W., & Nabholtz, J. M. (2002). An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer, 95(9), 2006–2016. https://doi.org/10.1002/cncr.10908

Carel, J. C., Eugster, E. A., Rogol, A., Ghizzoni, L., Palmert, M. R., ESPE-LWPES GnRH Analogs Consensus Conference Group, Antoniazzi, F., Berenbaum, S., Bourguignon, J. P., Chrousos, G. P., Coste, J., Deal, S., de Vries, L., Foster, C., Heger, S., Holland, J., Jahnukainen, K., Juul, A., Kaplowitz, P., Lahlou, N., … Wit, J. M. (2009). Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics, 123(4), e752–e762. https://doi.org/10.1542/peds.2008-1783

Cavalli, A., Bisi, A., Bertucci, C., Rosini, C., Paluszcak, A., Gobbi, S., Giorgio, E., Rampa, A., Belluti, F., Piazzi, L., Valenti, P., Hartmann, R. W., & Recanatini, M. (2005). Enantioselective nonsteroidal aromatase inhibitors identified through a multidisciplinary medicinal chemistry approach. Journal of medicinal chemistry, 48(23), 7282–7289. https://doi.org/10.1021/jm058042r

Cohen, P., Rogol, A. D., Deal, C. L., Saenger, P., Reiter, E. O., Ross, J. L., Chernausek, S. D., Savage, M. O., Wit, J. M., & 2007 ISS Consensus Workshop participants (2008). Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. The Journal of clinical endocrinology and metabolism, 93(11), 4210–4217. https://doi.org/10.1210/jc.2008-0509

Colussi, D. M., Parisot, C. Y., & Lefèvre, G. Y. (1998). Plasma protein binding of letrozole, a new nonsteroidal aromatase enzyme inhibitor. Journal of clinical pharmacology, 38(8), 727–735. https://doi.org/10.1002/j.1552-4604.1998.tb04813.x

Damiani, D., & Damiani, D. (2007). Pharmacological management of children with short stature: the role of aromatase inhibitors. Jornal de pediatria, 83(5 Suppl), S172–S177. https://doi.org/10.2223/JPED.1699

Dunkel, L., & Wickman, S. (2003). Novel treatment of short stature with aromatase inhibitors. The Journal of steroid biochemistry and molecular biology, 86(3-5), 345–356. https://doi.org/10.1016/s0960-0760(03)00344-3

Dunkel L. (2006). Use of aromatase inhibitors to increase final height. Molecular and cellular endocrinology, 254-255, 207–216. https://doi.org/10.1016/j.mce.2006.04.031

Dunkel L. (2009). Update on the role of aromatase inhibitors in growth disorders. Hormone research, 71 Suppl 1, 57–63. https://doi.org/10.1159/000178040

Geisler, J., Haynes, B., Anker, G., Dowsett, M., & Lønning, P. E. (2002). Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 20(3), 751–757. https://doi.org/10.1200/JCO.2002.20.3.751

Grumbach, M. M., & Auchus, R. J. (1999). Estrogen: consequences and implications of human mutations in synthesis and action. The Journal of clinical endocrinology and metabolism, 84(12), 4677–4694. https://doi.org/10.1210/jcem.84.12.6290

Hero, M., Norjavaara, E., & Dunkel, L. (2005). Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. The Journal of clinical endocrinology and metabolism, 90(12), 6396–6402. https://doi.org/10.1210/jc.2005-1392

Hero, M., Ankarberg-Lindgren, C., Taskinen, M. R., & Dunkel, L. (2006). Blockade of oestrogen biosynthesis in peripubertal boys: effects on lipid metabolism, insulin sensitivity, and body composition. European journal of endocrinology, 155(3), 453–460. https://doi.org/10.1530/eje.1.02226

Hero, M., Mäkitie, O., Kröger, H., Nousiainen, E., Toiviainen-Salo, S., & Dunkel, L. (2009). Impact of aromatase inhibitor therapy on bone turnover, cortical bone growth and vertebral morphology in pre- and peripubertal boys with idiopathic short stature. Hormone research, 71(5), 290–297. https://doi.org/10.1159/000208803

Hero, M., Toiviainen-Salo, S., Wickman, S., Mäkitie, O., & Dunkel, L. (2010). Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 25(7), 1536–1543. https://doi.org/10.1002/jbmr.56

Herrmann, B. L., Saller, B., Janssen, O. E., Gocke, P., Bockisch, A., Sperling, H., Mann, K., & Broecker, M. (2002). Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. The Journal of clinical endocrinology and metabolism, 87(12), 5476–5484. https://doi.org/10.1210/jc.2002-020498

Jones, M. E., Boon, W. C., McInnes, K., Maffei, L., Carani, C., & Simpson, E. R. (2007). Recognizing rare disorders: aromatase deficiency. Nature clinical practice. Endocrinology & metabolism, 3(5), 414–421. https://doi.org/10.1038/ncpendmet0477

Kamdem, L. K., Liu, Y., Stearns, V., Kadlubar, S. A., Ramirez, J., Jeter, S., Shahverdi, K., Ward, B. A., Ogburn, E., Ratain, M. J., Flockhart, D. A., & Desta, Z. (2010). In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. British journal of clinical pharmacology, 70(6), 854–869. https://doi.org/10.1111/j.1365-2125.2010.03791.x

Lee, J. M., Appugliese, D., Coleman, S. M., Kaciroti, N., Corwyn, R. F., Bradley, R. H., Sandberg, D. E., & Lumeng, J. C. (2009). Short stature in a population-based cohort: social, emotional, and behavioral functioning. Pediatrics, 124(3), 903–910. https://doi.org/10.1542/peds.2008-0085

Leschek, E. W., Jones, J., Barnes, K. M., Hill, S. C., & Cutler, G. B., Jr (1999). Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset. The Journal of clinical endocrinology and metabolism, 84(1), 175–178. https://doi.org/10.1210/jcem.84.1.5413

Linardi, A., Damiani, D., & Longui, C. A. (2017). The use of aromatase inhibitors in boys with short stature: what to know before prescribing?. Archives of endocrinology and metabolism, 61(4), 391–397. https://doi.org/10.1590/2359-3997000000284

Lønning, P., Pfister, C., Martoni, A., & Zamagni, C. (2003). Pharmacokinetics of third-generation aromatase inhibitors. Seminars in oncology, 30(4 Suppl 14), 23–32. https://doi.org/10.1016/s0093-7754(03)00305-1

Mauras, N., Attie, K. M., Reiter, E. O., Saenger, P., & Baptista, J. (2000). High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group. The Journal of clinical endocrinology and metabolism, 85(10), 3653–3660. https://doi.org/10.1210/jcem.85.10.6906

Mauras, N., Bell, J., Snow, B. G., & Winslow, K. L. (2005). Sperm analysis in growth hormone-deficient adolescents previously treated with an aromatase inhibitor: comparison with normal controls. Fertility and sterility, 84(1), 239–242. https://doi.org/10.1016/j.fertnstert.2005.02.012

Mauras, N., Gonzalez de Pijem, L., Hsiang, H. Y., Desrosiers, P., Rapaport, R., Schwartz, I. D., Klein, K. O., Singh, R. J., Miyamoto, A., & Bishop, K. (2008). Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. The Journal of clinical endocrinology and metabolism, 93(3), 823–831. https://doi.org/10.1210/jc.2007-1559

Mauras, N., Bishop, K., Merinbaum, D., Emeribe, U., Agbo, F., & Lowe, E. (2009). Pharmacokinetics and pharmacodynamics of anastrozole in pubertal boys with recent-onset gynecomastia. The Journal of clinical endocrinology and metabolism, 94(8), 2975–2978. https://doi.org/10.1210/jc.2008-2527

Mauras N. (2011). Strategies for maximizing growth in puberty in children with short stature. Pediatric clinics of North America, 58(5), 1167–x. https://doi.org/10.1016/j.pcl.2011.07.007

Mauras, N., Ross, J. L., Gagliardi, P., Yu, Y. M., Hossain, J., Permuy, J., Damaso, L., Merinbaum, D., Singh, R. J., Gaete, X., & Mericq, V. (2016). Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature. The Journal of clinical endocrinology and metabolism, 101(12), 4984–4993. https://doi.org/10.1210/jc.2016-2891

Mauras, N., Ross, J., & Mericq, V. (2023). Management of Growth Disorders in Puberty: GH, GnRHa, and Aromatase Inhibitors: A Clinical Review. Endocrine reviews, 44(1), 1–13. https://doi.org/10.1210/endrev/bnac014

McGrath, N., & O'Grady, M. J. (2015). Aromatase inhibitors for short stature in male children and adolescents. The Cochrane database of systematic reviews, 2015(10), CD010888. https://doi.org/10.1002/14651858.CD010888.pub2

Mericq, M. V., Eggers, M., Avila, A., Cutler, G. B., Jr, & Cassorla, F. (2000). Near final height in pubertal growth hormone (GH)-deficient patients treated with GH alone or in combination with luteinizing hormone-releasing hormone analog: results of a prospective, randomized trial. The Journal of clinical endocrinology and metabolism, 85(2), 569–573. https://doi.org/10.1210/jcem.85.2.6343

Merke, D. P., Keil, M. F., Jones, J. V., Fields, J., Hill, S., & Cutler, G. B., Jr (2000). Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia. The Journal of clinical endocrinology and metabolism, 85(3), 1114–1120. https://doi.org/10.1210/jcem.85.3.6462

Morishima, A., Grumbach, M. M., Simpson, E. R., Fisher, C., & Qin, K. (1995). Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. The Journal of clinical endocrinology and metabolism, 80(12), 3689–3698. https://doi.org/10.1210/jcem.80.12.8530621

Murai, K., Yamazaki, H., Nakagawa, K., Kawai, R., & Kamataki, T. (2009). Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes. Xenobiotica; the fate of foreign compounds in biological systems, 39(11), 795–802. https://doi.org/10.3109/00498250903171395

Murata, Y., Robertson, K. M., Jones, M. E., & Simpson, E. R. (2002). Effect of estrogen deficiency in the male: the ArKO mouse model. Molecular and cellular endocrinology, 193(1-2), 7–12. https://doi.org/10.1016/s0303-7207(02)00090-4

Neely, E. K., Kumar, R. B., Payne, S. L., Ranadive, S. A., & Suchet, D. I. (2014). Letrozole vs anastrozole for height augmentation in short pubertal males: first year data. The Journal of clinical endocrinology and metabolism, 99(11), 4086–4093. https://doi.org/10.1210/jc.2014-2432

Patry, G., Jarvi, K., Grober, E. D., & Lo, K. C. (2009). Use of the aromatase inhibitor letrozole to treat male infertility. Fertility and sterility, 92(2), 829.e1–829.e8292. https://doi.org/10.1016/j.fertnstert.2009.05.014

Pedrosa, L. F., de Oliveira, J. M., Thomé, P. R. V., Kochi, C., Damiani, D., & Longui, C. A. (2017). Height Increment and Laboratory Profile of Boys Treated With Aromatase Inhibitors With or Without Growth Hormone. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 49(10), 778–785. https://doi.org/10.1055/s-0043-116944

Pfister, C. U., Martoni, A., Zamagni, C., Lelli, G., De Braud, F., Souppart, C., Duval, M., & Hornberger, U. (2001). Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients. Biopharmaceutics & drug disposition, 22(5), 191–197. https://doi.org/10.1002/bdd.273

Precht, J. C., Schroth, W., Klein, K., Brauch, H., Krynetskiy, E., Schwab, M., & Mürdter, T. E. (2013). The letrozole phase 1 metabolite carbinol as a novel probe drug for UGT2B7. Drug metabolism and disposition: the biological fate of chemicals, 41(11), 1906–1913. https://doi.org/10.1124/dmd.113.053405

Queiroz, R.M.R. & Feferbaum, M. (2022). Metodologia da pesquisa em direito. Saraiva.

Robertson, K. M., O'Donnell, L., Jones, M. E., Meachem, S. J., Boon, W. C., Fisher, C. R., Graves, K. H., McLachlan, R. I., & Simpson, E. R. (1999). Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene. Proceedings of the National Academy of Sciences of the United States of America, 96(14), 7986–7991. https://doi.org/10.1073/pnas.96.14.7986

Rochira, V., Zirilli, L., Maffei, L., Premrou, V., Aranda, C., Baldi, M., Ghigo, E., Aimaretti, G., Carani, C., & Lanfranco, F. (2010). Tall stature without growth hormone: four male patients with aromatase deficiency. The Journal of clinical endocrinology and metabolism, 95(4), 1626–1633. https://doi.org/10.1210/jc.2009-1743

Saldanha, C. J., Duncan, K. A., & Walters, B. J. (2009). Neuroprotective actions of brain aromatase. Frontiers in neuroendocrinology, 30(2), 106–118. https://doi.org/10.1016/j.yfrne.2009.04.016

Santen, R. J., Brodie, H., Simpson, E. R., Siiteri, P. K., & Brodie, A. (2009). History of aromatase: saga of an important biological mediator and therapeutic target. Endocrine reviews, 30(4), 343–375. https://doi.org/10.1210/er.2008-0016

Saylam, B., Efesoy, O., & Cayan, S. (2011). The effect of aromatase inhibitor letrozole on body mass index, serum hormones, and sperm parameters in infertile men. Fertility and sterility, 95(2), 809–811. https://doi.org/10.1016/j.fertnstert.2010.09.021

Shulman, D. I., Francis, G. L., Palmert, M. R., Eugster, E. A., & Lawson Wilkins Pediatric Endocrine Society Drug and Therapeutics Committee (2008). Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development. Pediatrics, 121(4), e975–e983. https://doi.org/10.1542/peds.2007-2081

T'Sjoen, G. G., Giagulli, V. A., Delva, H., Crabbe, P., De Bacquer, D., & Kaufman, J. M. (2005). Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. The Journal of clinical endocrinology and metabolism, 90(10), 5717–5722. https://doi.org/10.1210/jc.2005-0982

Topor, L. S., Feldman, H. A., Bauchner, H., & Cohen, L. E. (2010). Variation in methods of predicting adult height for children with idiopathic short stature. Pediatrics, 126(5), 938–944. https://doi.org/10.1542/peds.2009-3649

Turner, K. J., Morley, M., Atanassova, N., Swanston, I. D., & Sharpe, R. M. (2000). Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility. The Journal of endocrinology, 164(2), 225–238. https://doi.org/10.1677/joe.0.1640225

Turkistani, A., & Marsh, S. (2012). Pharmacogenomics of third-generation aromatase inhibitors. Expert opinion on pharmacotherapy, 13(9), 1299–1307. https://doi.org/10.1517/14656566.2012.687721

Wickman, S., Sipilä, I., Ankarberg-Lindgren, C., Norjavaara, E., & Dunkel, L. (2001). A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet (London, England), 357(9270), 1743–1748. https://doi.org/10.1016/S0140-6736(00)04895-9

Wickman, S., Kajantie, E., & Dunkel, L. (2003). Effects of suppression of estrogen action by the p450 aromatase inhibitor letrozole on bone mineral density and bone turnover in pubertal boys. The Journal of clinical endocrinology and metabolism, 88(8), 3785–3793. https://doi.org/10.1210/jc.2002-021643

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

Wit, J. M., Hero, M., & Nunez, S. B. (2011). Aromatase inhibitors in pediatrics. Nature reviews. Endocrinology, 8(3), 135–147. https://doi.org/10.1038/nrendo.2011.161

Published

03/02/2023

How to Cite

CRUZ, M. O. .; SAAB, A. R. M. . Use of aromatase inhibitors for height improvement in boys: a literature review . Research, Society and Development, [S. l.], v. 12, n. 2, p. e19112240181, 2023. DOI: 10.33448/rsd-v12i2.40181. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/40181. Acesso em: 24 apr. 2024.

Issue

Section

Health Sciences