Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia

Abstract

Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved.

Letrozole vs Anastrozole for Height Augmentation in Short Pubertal Males: First Year Data

“…Hormone responses to AI in rodents appear to be different from humans, in that gonadotropin and testosterone concentrations do not increase (42)(43)(44)(45) as they do in pubertal boys. Nonetheless, several animal models of reduced aromatization provide specific reasons for caution in human applications of AI.…”

“…Addition of anastrozole to drinking water throughout the rat lifespan (43) resulted in a persistent decrease in overall body weight and fat pad weight, although testicular weight increased. Rats fed letrozole from day 30 to 90 (45), broadly encompassing pubertal growth and development, had reductions in body weight (Ϫ37.5%), percent fat mass, crown-rump length, tibial length, and IGF-1 levels during treatment and into adulthood at day 150. Testes were enlarged relative to the reduced body weight.…”

“…Focal prostatic hyperplasia and a smaller prostate anterior lobe (without reduction in other lobes) were observed in treated rats. Additionally, persistent treatment-induced alterations in bone geometry were detected by PQCT, whereas volumetric bone mineral density (BMD) by DEXA was not affected, leading the investigators to suggest that DEXA may miss potential detrimental changes in bone geometry (45).…”

Aromatase inhibitors in pediatrics

“…43 Exemestane or letrozole treatment of young male rats caused osteopenia and prostatic hyperplasia and reduced body weight, tail length and IGF-1 levels. 44,45 By contrast, in male mice, letrozole increased body weight and tail length gain, the width of the epiphyseal growth plates and GH levels. 46 Anastrozole administration to adult male rats had no effect on the number of Sertoli cells or germ cells, or on the volume of the seminiferous epithelium, tubule lumens or interstitium.…”

“…39 Increased abdominal fat deposition and insulin resistance was present in both sexes. 41 Studies on the effect of gonadectomy, chemical castration with gonadotropin-releasing hormone (GnRH) analogues 42 or use of aromatase inhibitors [43][44][45] in rats have also shown sexual dimorphism. In male rats, the nonsteroidal aromatase inhibitor vorozole decreased body weight and BMD, but femoral length was normal.…”