Background: As the evidence for the role of oestrogens in epiphyseal closure appears unequivocal, we hypothesized that boys with constitutional delay of puberty would attain greater adult height if oestrogen action was suppressed. Methods: We conducted a randomized, double-blind, placebo-controlled study in which we treated boys with constitutional delay of puberty with testosterone plus placebo or testosterone plus a potent fourth-generation aromatase inhibitor, letrozole. Findings: Letrozole effectively inhibited oestrogen synthesis. The 17β-oestradiol concentrations increased in the untreated group and in the testosterone/placebo-treated group, but in the testosterone/letrozole-treated group no such increase was observed until letrozole treatment was discontinued. Testosterone concentrations were threefold higher in the testosterone/letrozole-treated group than in the other groups. Within 18 months, bone age had advanced by 1.1 ± 0.3 years in the untreated group and by 1.7 ± 0.3 years in the testosterone/placebo-treated group, but only by 0.9 ± 0.2 years in the testosterone/letrozole-treated group (p = 0.02 between treatment groups). Predicted adult height did not change significantly in the untreated group and in the testosterone/placebo-treated group, whereas in the testosterone/letrozole-treated group the increase was 5.1 ± 1.2 cm (p = 0.004). Conclusions: Our findings suggest that, if oestrogen action is inhibited in growing adolescents, adult height will increase. This observation provides a rationale for studies aimed at delaying bone maturation in several growth disorders.

Keywords:
Oestrogens, Aromatase, Puberty, Growth, Growth plate, Gonadotrophins, Inhibin
1.
Caruso-Nicoletti M, Cassorla F, Skerda M, Ross JL, Loriaux DL, Cutler GB Jr: Short term, low dose estradiol accelerates ulnar growth in boys. J Clin Endocrinol Metab 1985;61:896–898.
2.
Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS: Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331:1056–1061.
3.
Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K: Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689–3698.
4.
Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER: Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997;337:91–95.
5.
Bilezikian JP, Morishima A, Bell J, Grumbach MM: Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 1998;339:599–603.
6.
Crowne EC, Shalet SM, Wallace WH, Eminson DM, Price DA: Final height in boys with untreated constitutional delay in growth and puberty. Arch Dis Child 1990;65:1109–1112.
7.
Albanese A, Stanhope R: Predictive factors in the determination of final height in boys with constitutional delay of growth and puberty. J Pediatr 1995;126:545–550.
8.
Albanese A, Stanhope R: Does constitutional delayed puberty cause segmental disproportion and short stature? Eur J Pediatr 1993;152:293–296.
9.
LaFranchi S, Hanna CE, Mandel SH: Constitutional delay of growth: expected versus final adult height. Pediatrics 1991;87:82–87.
10.
Blethen SL, Gaines S, Weldon V: Comparison of predicted and adult heights in short boys: effect of androgen therapy. Pediatr Res 1984;18:467–469.
11.
Martin MM, Martin AL, Mossman KL: Testosterone treatment of constitutional delay in growth and development: effect of dose on predicted versus definitive height. Acta Endocrinol Suppl (Copenh) 1986;279:147–152.
12.
Wickman S, Sipilä I, Ankarber-Lindgren C, Norjavaara E, Dunkel L: A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet 2001;357:1743–1748.
13.
Ojajärvi P: The adolescent Finnish child, a longitudinal study of the anthropometry, physical development and physiological changes during puberty. Thesis, University of Helsinki, Helsinki, 1982.
14.
Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist, ed 2. Stanford, Stanford University Press, 1959.
15.
Bayley N, Pinneau SR: Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr 1952;40:423–441.
16.
Tanner JM: Growth at Adolescence, ed 2. Oxford, Blackwell Scientific, 1962.
17.
Hansen PF, With TK: Clinical measurements of the testes in boys and men. Acta Med Scand 1952;142(suppl 266):457–465.
18.
Norjavaara E, Ankarberg C, Albertsson-Wikland K: Diurnal rhythm of 17 beta-estradiol secretion throughout pubertal development in healthy girls: evaluation by a sensitive radioimmunoassay. J Clin Endocrinol Metab 1996;81:4095–4102.
19.
Dunkel L, Alfthan H, Stenman UH, Perheentupa J: Gonadal control of pulsatile secretion of luteinizing hormone and follicle-stimulating hormone in prepubertal boys evaluated by ultrasensitive time-resolved immunofluorometric assays. J Clin Endocrinol Metab 1990;70:107–114.
20.
Apter D, Jänne O, Karvonen P, Vihko R: Simultaneous determination of five sex hormones in human serum by radioimmunoassay after chromatography on Lipidex-5000. Clin Chem 1976;22:32–38.
21.
Trunet PF, Mueller P, Bhatnagar AS, Dickes I, Monnet G, White G: Open dose-finding study of a new potent and selective nonsteroidal aromatase inhibitor, CGS 20 267, in healthy male subjects. J Clin Endocrinol Metab 1993;77:319–323.
22.
Joss EE, Schmidt HA, Zuppinger KA: Oxandrolone in constitutionally delayed growth, a longitudinal study up to final height. J Clin Endocrinol Metab 1989;69:1109–1115.
23.
Metzger DL, Kerrigan JR: Estrogen receptor blockade with tamoxifen diminishes growth hormone secretion in boys: evidence for a stimulatory role of endogenous estrogens during male adolescence. J Clin Endocrinol Metab 1994;79:513–518.
24.
Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA: Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997;138:863–870.
25.
Kletter GB, Padmanabhan V, Beitins IZ, Marshall JC, Kelch RP, Foster CM: Acute effects of estradiol infusion and naloxone on luteinizing hormone secretion in pubertal boys. J Clin Endocrinol Metab 1997;82:4010–4014.
26.
Kerrigan JR, Veldhuis JD, Rogol AD: Androgen-receptor blockade enhances pulsatile luteinizing hormone production in late pubertal males: evidence for a hypothalamic site of physiologic androgen feedback action. Pediatr Res 1994;35:102–106.
27.
Veldhuis JD, Rogol AD, Samojlik E, Ertel NH: Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man. J Clin Invest 1984;74:47–55.
28.
Finkelstein JS, O’Dea LS, Whitcomb RW, Crowley WF Jr: Sex steroid control of gonadotropin secretion in the human male. II. Effects of estradiol administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab 1991;73:621–628.
29.
Nachtigall LB, Boepple PA, Seminara SB, Khoury RJ, Sluss PM, Lecain AE, Crowley WF Jr: Inhibin B secretion in males with gonadotropin-releasing hormone (GnRH) deficiency before and during long-term GnRH replacement: relationship to spontaneous puberty, testicular volume, and prior treatment – a clinical research center study. J Clin Endocrinol Metab 1996;81:3520–3525.
© 2002 S. Karger AG, Basel
2002
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.