Background: Systemic administration of the nonaromatizable androgen oxandrolone stimulates growth in girls with Turner syndrome and boys with a constitutional delay of growth and puberty. It is unknown if oxandrolone acts locally at the growth plate level to stimulate longitudinal bone growth. Methods: Metatarsal bones from female and male rat fetuses (day E20) were cultured for 14 days in the presence of oxandrolone, testosterone or the androgen receptor (AR) antagonist flutamide with/without insulin-like growth-factor-I (IGF-I) or charcoal-treated serum. Results: The AR was found to be expressed in both male and female fetal rat metatarsal bones. Neither oxandrolone nor testosterone had any effect on metatarsal bone growth when tested at a wide concentration range (1 nM to 10 μM), not even in the presence of IGF-I (100 ng/ml) or charcoal-treated serum (10%). Bone growth was also unaffected when the AR was blocked by flutamide. Control experiments confirmed that metatarsal bone growth was significantly stimulated by IGF-I (p < 0.001). Conclusion: Modulation of AR activity in the fetal rat growth plate does not affect linear bone growth. Extrapolating from these in vitro data, it could be speculated that oxandrolone stimulates longitudinal bone growth in treated children by acting indirectly rather than directly through AR activation in growth plate chondrocytes.

1.
Ren SG, Malozowski S, Sanchez P, Sweet DE, Loriaux DL, Cassorla F: Direct administration of testosterone increases rat tibial epiphyseal growth plate width. Acta Endocrinol (Copenh) 1989;121:401–405.
2.
Tivesten A, Moverare-Skrtic S, Chagin A, Venken K, Salmon P, Vanderschueren D, Sävendahl L, Holmäng A, Ohlsson C: Additive protective effects of estrogen and androgen treatment on trabecular bone in ovariectomized rats. J Bone Miner Res 2004;19:1833–1839.
3.
Van Der Eerden BC, Van De Ven J, Lowik CW, Wit JM, Karperien M: Sex steroid metabolism in the tibial growth plate of the rat. Endocrinology 2002;143:4048–4055.
4.
De Luca F, Argente J, Cavallo L, Crowne E, Delemarre-van de Waal HA, De Sanctis C, Di Maio S, Norjavaara E, Oostdijk W, Severi F, Tonini G, Trifirò G, Voorhoeve PG, Wu F: Management of puberty in constitutional delay of growth and puberty. J Pediatr Endocrinol Metab 2001;14:953–957.
5.
Batch J: Turner syndrome in childhood and adolescence. Best Pract Res Clin Endocrinol Metab 2002;16:465–482.
6.
Schroor EJ, van Weissenbruch MM, Knibbe P, Delemarre-van de Waal HA: The effect of prolonged administration of an anabolic steroid (oxandrolone) on growth in boys with constitutionally delayed growth and puberty. Eur J Pediatr 1995;154:953–957.
7.
Tse WY, Buyukgebiz A, Hindmarsh PC, Stanhope R, Preece MA, Brook CG: Long-term outcome of oxandrolone treatment in boys with constitutional delay of growth and puberty. J Pediatr 1990;117:588–591.
8.
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.
9.
Lampit M, Hochberg Z: Androgen therapy in constitutional delay of growth. Horm Res 2003;59:270–275.
10.
Crowne EC, Wallace WH, Moore C, Mitchell R, Robertson WH, Holly JM, Shalet SM: Effect of low dose oxandrolone and testosterone treatment on the pituitary-testicular and GH axes in boys with constitutional delay of growth and puberty. Clin Endocrinol (Oxf) 1997;46:209–216.
11.
Malhotra A, Poon E, Tse WY, Pringle PJ, Hindmarsh PC, Brook CG: The effects of oxandrolone on the growth hormone and gonadal axes in boys with constitutional delay of growth and puberty. Clin Endocrinol (Oxf) 1993;38:393–398.
12.
Ulloa-Aguirre A, Blizzard RM, Garcia-Rubi E, Rogol AD, Link K, Christie CM, Johnson ML, Veldhuis JD: Testosterone and oxandrolone: a nonaromatizable androgen, specifically amplify the mass and rate of growth hormone (GH) secreted per burst without altering GH secretory burst duration or frequency or the GH half-life. J Clin Endocrinol Metab 1990;71:846–854.
13.
Abu EO, Horner A, Kusec V, Triffitt JT, Compston JE: The localization of androgen receptors in human bone. J Clin Endocrinol Metab 1997;82:3493–3497.
14.
Nilsson O, Chrysis D, Pajulo O, Boman A, Holst M, Rubinstein J, Martin Ritzén E, Sävendahl L: Localization of estrogen receptors-alpha and -beta and androgen receptor in the human growth plate at different pubertal stages. J Endocrinol 2003;177:319–326.
15.
Oz OK, Millsaps R, Welch R, Birch J, Zerwekh JE: Expression of aromatase in the human growth plate. J Mol Endocrinol 2001;27:249–253.
16.
Mancilla EE, De Luca F, Uyeda JA, Czerwiec FS, Baron J: Effects of fibroblast growth factor-2 on longitudinal bone growth. Endocrinology 1998;139:2900–2904.
17.
Martensson K, Chrysis D, Sävendahl L: Interleukin-1beta and TNF-alpha act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones. J Bone Miner Res 2004;19:1805–1812.
18.
Chagin AS, Chrysis D, Takigawa M, Ritzen EM, Sävendahl L: Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis. J Endocrinol 2006;188:193–203.
19.
Chagin AS, Karimian E, Zaman F, Takigawa M, Chrysis D, Sävendahl L: Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones. Bone 2007;40:1415–1424.
20.
Mushtaq T, Bijman P, Ahmed SF, Farquharson C: Insulin-like growth factor-I augments chondrocyte hypertrophy and reverses glucocorticoid-mediated growth retardation in fetal mice metatarsal cultures. Endocrinology 2004;145:2478–2486.
21.
Veldhuis JD, Roemmich JN, Rogol AD: Gender and sexual maturation-dependent contrasts in the neuroregulation of growth hormone secretion in prepubertal and late adolescent males and females: a general clinical research center-based study. J Clin Endocrinol Metab 2000;85:2385–2394.
22.
Link K, Blizzard RM, Evans WS, Kaiser DL, Parker MW, Rogol AD: The effect of androgens on the pulsatile release and the twenty-four-hour mean concentration of growth hormone in peripubertal males. J Clin Endocrinol Metab 1986;62:159–164.
23.
Krohn K, Haffner D, Hügel U, Himmele R, Klaus G, Mehls O, Schaefer F: 1,25(OH)2D3 and dihydrotestosterone interact to regulate proliferation and differentiation of epiphyseal chondrocytes. Calcif Tissue Int 2003;73:400–410.
24.
Corvol MT, Carrascosa A, Tsagris L, Blanchard O, Rappaport R: Evidence for a direct in vitro action of sex steroids on rabbit cartilage cells during skeletal growth: influence of age and sex. Endocrinology 1987;120:1422–1429.
25.
Blanchard O, Tsagris L, Rappaport R, Duval-Beaupere G, Corvol M: Age-dependent responsiveness of rabbit and human cartilage cells to sex steroids in vitro. J Steroid Biochem Mol Biol 1991;40:711–716.
26.
Balsamo A, Wasniewska M, Di Pasquale G, Salzano G, Baronio F, Bombaci S, De Luca F: Birth length and weight in congenital adrenal hyperplasia according to the different phenotypes. Eur J Pediatr 2006;165:380–383.
27.
Picherit C, Coxam V, Oudadesse H, Martini B, Gaumet N, Davicco MJ, Lebecque P, Miller S, Irrigaray JL, Barlet JP: Dihydrotestosterone prevents glucocorticoid-negative effects on fetal rat metatarsal bone in vitro. Biol Neonate 2000;77:181–190.
28.
Carrascosa A, Audi L, Ferrandez MA, Ballabriga A: Biological effects of androgens and identification of specific dihydrotestosterone-binding sites in cultured human fetal epiphyseal chondrocytes. J Clin Endocrinol Metab 1990;70:134–140.
29.
Schwartz Z, Soskolne WA, Neubauer T, Goldstein M, Adi S, Ornoy A: Direct and sex-specific enhancement of bone formation and calcification by sex steroids in fetal mice long bone in vitro (biochemical and morphometric study). Endocrinology 1991;129:1167–1174.
30.
Maor G, Segev Y, Phillip M: Testosterone stimulates insulin-like growth factor-I and insulin-like growth factor-I-receptor gene expression in the mandibular condyle: a model of endochondral ossification. Endocrinology 1999;140:1901–1910.
31.
van der Eerden BC, van Til NP, Brinkmann AO, Lowik CW, Wit JM, Karperien M: Gender differences in expression of androgen receptor in tibial growth plate and metaphyseal bone of the rat. Bone 2002;30:891–896.
32.
Kapur SP, Reddi AH: Influence of testosterone and dihydrotestosterone on bone-matrix induced endochondral bone formation. Calcif Tissue Int 1989;44:108–113.
33.
Sylvia VL, Gay I, Hardin R, Dean DD, Boyan BD, Schwartz Z: Rat costochondral chondrocytes produce 17beta-estradiol and regulate its production by 1alpha,25(OH)(2)D(3). Bone 2002;30:57–63.
34.
Raz P, Nasatzky E, Boyan BD, Ornoy A, Schwartz Z: Sexual dimorphism of growth plate prehypertrophic and hypertrophic chondrocytes in response to testosterone requires metabolism to dihydrotestosterone (DHT) by steroid 5-alpha reductase type 1. J Cell Biochem 2005;95:108–119.
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