The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice

Abstract

Sex hormones may influence longitudinal growth, either indirectly, by affecting the growth-hormone-insulin-like growth factor I (IGF-I) axis, or directly, by affecting changes within the epiphyseal growth plate (EGP). The aim of the present study was to investigate the effects of letrozole, an aromatase inhibitor, on longitudinal growth and changes in the EGP in vivo. Eighteen peripubertal male mice were divided into three groups. The first group was killed at baseline, the second was injected with letrozole (Femara) s.c., 2 mg/kg body weight/day, for 10 days, and the third was injected with the vehicle alone. Serum testosterone levels were found to be significantly higher in the treated group than in the controls. Letrozole induced a significant increase in body weight, tail length and serum growth hormone level, but had no significant effect on the level of serum IGF-I. On histomorphometric study, there was a significant increase (12%) in EGP height in the treated animals compared with controls. Immunohistochemistry showed a 3·4-fold letrozole-induced increase in the proliferation of the EGP chondrocytes, as estimated by the number of proliferation cell nuclear antigen-stained cells, and a decrease in the differentiation of the EGP chondrocytes, as estimated by type X collagen staining. Letrozole did not interfere with type II collagen levels. The study group also showed a twofold increase in the number of IGF-I receptor-positive cells compared with controls. In conclusion, the aromatase inhibitor, letrozole, appears to increase the linear growth potential of the EGP in mice.

Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis

“…It should be emphasized that aromatase expression was mainly detected in adolescent humans and pubertal animals but very weak activity and expression of aromatase was detected before sexual maturation ( Van Der Eerden et al 2002). Interestingly, our observation of P450 aromatase expression in hypertrophic chondrocytes of fetal rat metatarsal bones is in line with several in vivo studies in different species (Oz et al 2001, Van Der Eerden et al 2002, Eshet et al 2004. Several key enzymes needed for estrogen synthesis, including STS and 17 -HSD, has been demonstrated in rat growth plate cartilage (Van Der Eerden et al 2002).…”

“…In rodents, in contrast to humans, estrogen has a well known inhibitory effect on longitudinal growth. Treatment of mice with letrozole increases tibia length and epiphyseal growth plate height (Eshet et al 2004). However, the effect was accompanied by an 8-fold increase in serum GH and a 6-fold increase in serum testosterone, which most likely reflects the systemic actions of the letrozole treatment.…”

Vertebral morphology in aromatase inhibitor–treated males with idiopathic short stature or constitutional delay of puberty

“…In juvenile rabbits and mice, estrogen treatment reduces chondrocyte proliferation and growth plate height, whereas letrozole may decrease the differentiation rate of growth plate chondrocytes and increase growth plate height. (17,18) It remains unclear whether human growth plates respond similarly to estrogen deprivation. In addition, it is unclear if such growth plate changes could predispose to vertebral deformities.…”

The Effects of Crude Aqueous and Alcohol Extracts of <em>Aloe Vera</em> on Growth and Abdominal Viscera of Suckling Rats

“…Tibial length has been used as a more accurate indicator of linear growth compared to body mass gain, which can be influenced by several factors including food intake and hydration status (Eshet et al, 2004). Growth hormone (GH) is a key hormone for promotion of growth and development (Tisi et al, 2005).…”