Are aromatase inhibitors in boys with predicted short stature and/or rapidly advancing bone age effective and safe?
-
Jessica A. Ferris
and
Mitchell E. Geffner
Abstract
Background:
The aim of this study was to assess aromatase inhibitor (AI) efficacy in increasing predicted adult height (PAH) and to describe clinical and biochemical safety profiles of AI-treated boys.
Methods:
A retrospective chart review was conducted at an academic children’s hospital endocrinology clinic. Twenty-one boys with predicted short stature and/or rapidly advancing bone age, divided as Tanner stage (TS) I–III Group 1 (G1, n=9) and TS IV–V Group 2 (G2, n=12), were treated with AIs, either letrozole or anastrozole (mean duration, G1: 2.4 years and G2: 0.9 years). Primary outcomes included PAH, hormonal/biochemical analytes, and clinical data.
Results:
PAH did not significantly change in either group. Mean peak testosterone significantly increased from baseline to 650±458 ng/dL (p=0.008) in G1 and to 1156±302 ng/dL (p=0.002) in G2. Estradiol did not significantly change in either group. Compared to baseline, G2 showed increased mean FSH (p=0.002), LH (p=0.002), hematocrit (p=0.0001), body mass index (BMI) z-score (p=0.0005), and acne (p=0.01).
Conclusions:
AIs did not increase PAH, regardless of TS. Boys in late puberty had significant increases in testosterone, gonadotropins, hematocrit, acne, and BMI, but no reduction in estradiol. The potential consequences of these findings are concerning and require long-term study, especially if AIs are started in late puberty.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Smith E, Boyd J, Frank G, Takahashi H, Cohen R, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331:1056–61.10.1056/NEJM199410203311604Search in Google Scholar
2. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997;337:91–5.10.1056/NEJM199707103370204Search in Google Scholar
3. MacGillivray M, Morishima A, Conte F, Grumbach M, Smith E. Pediatric endocrinology update: an overview. Horm Res 1998;49(suppl 1):2–8.10.1159/000053061Search in Google Scholar
4. Wickman S, Sipila I, Ankarberg-Lindgren C, Norjavaara E, Dunkel L. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomized controlled trial. Lancet 2001;357:1743–8.10.1016/S0140-6736(00)04895-9Search in Google Scholar
5. Hero M, Wickman S, Dunkel L. Treatment with the aromatase inhibitor letrozole during adolescence increases near-final adult height in boys with constitutional delay of puberty. Clin Endocrinol 2006;64:510–3.10.1111/j.1365-2265.2006.02499.xSearch in Google Scholar PubMed
6. Hero M, Toiviainen-Salo S, Wickman S, Makitie O, Dunkel L. Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty. J Bone Miner Res 2010;25:1536–43.10.1002/jbmr.56Search in Google Scholar PubMed
7. Wit J, Hero M, Nunez S. Aromatase inhibitors in pediatrics. Nat Rev Endocrinol 2012;8:135–47.10.1038/nrendo.2011.161Search in Google Scholar PubMed
8. Hero M, Norjavaara E, Dunkel L. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. J Clin Endocrinol Metab 2005;90:6396–402.10.1210/jc.2005-1392Search in Google Scholar PubMed
9. Salehpour S, Alipour P, Razzaghy-Azar M, Ardeshirpour L, Shamshiri A, et al. A double-blind, placebo-controlled comparison of letrozole to oxandrolone effects upon growth and puberty of children with constitutional delay of puberty and idiopathic short stature. Horm Res Paediatr 2010;74:428–35.10.1159/000315482Search in Google Scholar PubMed
10. Mauras N, Gonzalez de Pijem L, Hsiang H, Desrosiers P, Rapaport R, et al. Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab 2007;93:823–31.10.1210/jc.2007-1559Search in Google Scholar PubMed PubMed Central
11. Neely E, Kumar R, Payne S, Ranadive S, Suchet D. Letrozole versus anastrozole for height augmentation in short pubertal males: first year data. J Clin Endocrinol Metab 2014;99:4086–93.10.1210/jc.2014-2432Search in Google Scholar PubMed
12. Shams K, Cameo T, Fennoy I, Hassoun A, Lerner S, et al. Outcome analysis of aromatase inhibitor therapy to increase adult height in males with predicted short adult stature and/or rapid pubertal progess: a retrospective chart review. J Pediatr Endocrinol Metab 2014;27:725–30.10.1515/jpem-2013-0470Search in Google Scholar PubMed PubMed Central
13. Mauras N, Ross J, Gagliardi P, Yu Y, Hossain J, et al. Randomized trial of aromatase inhibitors, growth hormone or combination in pubertal boys with idiopathic short stature. J Clin Endocrinol Metab 2016;101:4984–93.10.1210/jc.2016-2891Search in Google Scholar PubMed PubMed Central
14. McGrath N, O’Grady MJ. Aromatase inhibitors for short stature in male children and adolescents. Cochrane Database Syst Rev 2015; Art. No.: CD010888. DOI: 10.1002/14651858.CD010888.pub2.10.1002/14651858.CD010888.pub2Search in Google Scholar PubMed
15. Geffner M. For debate: aromatase inhibitors to augment height: have we lost our inhibitions? Pediatr Endocrinol Rev 2008;5:756–9.Search in Google Scholar
16. Geffner M. Aromatase inhibitors to augment height: continued caution and study required. J Clin Res Pediatr Endocrinol 2009;1:256–61.10.4274/jcrpe.v1i6.256Search in Google Scholar PubMed PubMed Central
17. Greulich W, Pyle S. Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford, CA: Stanford University Press, 1959.10.1097/00000441-195909000-00030Search in Google Scholar
18. Hero M, Ankarberg-Lindgren C, Taskinen M, Dunkel L. Blockage of oestrogen biosynthesis in peripubertal boys: effects on lipid metabolism, insulin sensitivity, and body composition. Eur J Endocrinol 2006;155:453–60.10.1530/eje.1.02226Search in Google Scholar PubMed
19. Mauras N, O’Brien K, Klein K, Hayes V. Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab 2000;85:2370–7.10.1210/jc.85.7.2370Search in Google Scholar
20. Wickman S, Dunkel L. Inhibition of P450 aromatase enhances gonadotropin secretion in early and midpubertal boys: evidence for a pituitary site of action of endogenous E. J Clin Endocrinol Metab 2001;86:4887–94.10.1210/jcem.86.10.7927Search in Google Scholar PubMed
21. Rhoden E, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482–92.10.1056/NEJMra022251Search in Google Scholar PubMed
22. Shahidi N. Androgens and erythropoiesis. N Engl J Med 1973;289:72–80.10.1056/NEJM197307122890205Search in Google Scholar PubMed
23. Hero M, Wickman S, Hanhijarvi R, Siimes M, Dunkel L. Pubertal upregulation of erythropoiesis in boys is determined primarily by androgen. J Pediatr 2005;146:245–52.10.1016/j.jpeds.2004.09.002Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
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- Are aromatase inhibitors in boys with predicted short stature and/or rapidly advancing bone age effective and safe?
- Increased prevalence of bicuspid aortic valve in Turner syndrome links with karyotype: the crucial importance of detailed cardiovascular screening
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- Case Reports
- Adrenarche unmasks compound heterozygous 3β-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY
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Articles in the same Issue
- Frontmatter
- Review
- Adrenocortical neoplasms in adulthood and childhood: distinct presentation. Review of the clinical, pathological and imaging characteristics
- Original Articles
- Assessment of health-related quality of life in Egyptian adolescents with type 1 diabetes: DEMPU survey
- Non-HDL-cholesterol and C-reactive protein in children and adolescents with type 1 diabetes
- Nutritional status and metabolic profile in neurologically impaired pediatric surgical patients
- Vascular risk factors are associated with retinal arteriolar narrowing and venular widening in children and adolescents with type 1 diabetes
- Are aromatase inhibitors in boys with predicted short stature and/or rapidly advancing bone age effective and safe?
- Increased prevalence of bicuspid aortic valve in Turner syndrome links with karyotype: the crucial importance of detailed cardiovascular screening
- Resting energy expenditure in girls with Turner syndrome
- AMH levels in girls with various pubertal problems
- Bone age in unilateral spastic cerebral palsy: is there a correlation with hand function and limb length?
- Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism
- A novel DAX-1 mutation in two male siblings presenting with precocious puberty and late-onset hypogonadotropic hypogonadism
- Case Reports
- Adrenarche unmasks compound heterozygous 3β-hydroxysteroid dehydrogenase deficiency: c.244G>A (p.Ala82Thr) and the novel 931C>T (p.Gln311*) variant in a non-salt wasting, severely undervirilised 46XY
- Three cases of Gordon syndrome with dominant KLHL3 mutations
- Unexplained cyanosis caused by hepatopulmonary syndrome in a girl with APECED syndrome
