title: 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.
authors.affiliation: Department of Endocrinology and Diabetes, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia.
authors.forename: Anurag
authors.initials: A
authors.lastname: Bajpai
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Simm
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McPherson
authors.forename: Vincenzo C
authors.initials: VC
authors.lastname: Russo
authors.forename: Walid J
authors.initials: WJ
authors.lastname: Azar
authors.forename: John D
authors.initials: JD
authors.lastname: Wark
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.forename: George A
authors.initials: GA
authors.lastname: Werther
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors / Q000009:adverse effects*; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D001846:Bone Development / Q000187:drug effects* / Q000502:physiology; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D002648:Child; D006130:Growth Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D000077289:Letrozole; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009570:Nitriles / Q000009:adverse effects; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000209:etiology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012741:Sexual Maturation / Q000502:physiology; D013737:Testis / Q000187:drug effects / Q000473:pathology; D014230:Triazoles / Q000009:adverse effects
chemical_list: D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D007986:Luteinizing Hormone