Chronic aromatase inhibition increases ventral hippocampal neurogenesis in middle-aged female mice

Abstract

Letrozole, a third-generation aromatase inhibitor, prevents the production of estrogens in the final step in conversion from androgens. Due to its efficacy at suppressing estrogens, letrozole has recently taken favor as a first-line adjuvant treatment for hormone-responsive breast cancer in middle-aged women. Though patient response to letrozole has generally been positive, there is conflicting evidence surrounding its impact on the development of depression. It is possible that letrozoles potential adverse effects on mood are a result of the impact of hormonal fluctuations on neurogenesis in the hippocampus. Thus, to clarify the effects of letrozole on the hippocampus and behavior, we examined how chronic administration affects hippocampal neurogenesis and depressive-like behaviour in middle-aged, intact female mice. Mice were given either letrozole (1mg/kg) or vehicle by injection (ip) daily for 3 weeks. Depressive-like behaviour was assessed during the last 3 days of treatment using the forced swim test, tail suspension test, and sucrose preference test, and the production of new neurons was quantified using the immature neuronal marker, doublecortin (DCX). We found that letrozole increased DCX expression and maturation in the dentate gyrus, but had no significant effect on depressive-like behaviour. Our findings suggest that a reduction in circulating estrogens in middle-aged females increases hippocampal neurogenesis without any adverse impact on behavior; as such, this furthers our understanding of how estrogens modulate neurogenesis, and to the rationale for the utilization of letrozole in the clinical management of breast cancer.