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

Abstract

28 29 Letrozole, a third-generation aromatase inhibitor, prevents the production of estrogens in 30 the final step in conversion from androgens. Due to its efficacy at suppressing estrogens, 31letrozole has recently taken favor as a first-line adjuvant treatment for hormone-responsive breast 32 cancer in middle-aged women. Though patient response to letrozole has generally been positive, 33there is conflicting evidence surrounding its effects on the development of depression. It is 34 possible that the potential adverse effects of letrozole on mood are a result of the impact of 35 hormonal fluctuations on neurogenesis in the hippocampus. Thus, to clarify the effects of 36 letrozole on the hippocampus and behavior, we examined how chronic administration affects 37 hippocampal neurogenesis and depressive-like behavior in middle-aged, intact female mice. 38Mice were given either letrozole (1mg/kg) or vehicle by injection (i.p.) daily for 3 weeks. 39Depressive-like behavior was assessed during the last 3 days of treatment using the forced swim 40test, tail suspension test, and sucrose preference test. The production of new neurons was 41 quantified using the immature neuronal marker doublecortin (DCX), and cell proliferation was 42 quantified using the endogenous marker Ki67. We found that letrozole increased DCX and Ki67 43 expression and maturation in the dentate gyrus, but had no significant effect on depressive-like 44behavior. Our findings suggest that a reduction in estrogens in middle-aged females increases 45 hippocampal neurogenesis without any adverse impact on depressive-like behavior; as such, this 46 furthers our understanding of how estrogens modulate neurogenesis, and to the rationale for the 47 utilization of letrozole in the clinical management of breast cancer. 48 49 50

Androgens enhance adult hippocampal neurogenesis in males but not females in an age-dependent manner

“…169DHT increased the proportion of BrdU/NeuN colabelled cells, an effect mostly driven by the 170 middle-aged females, and overall as expected, the proportion of new cells that express mature 171 neuronal protein decreased with age. In middle-aged female mice letrozole, an aromatase 172 inhibitor blocking the conversion of androgens to estrogens, increases hippocampal neurogenesis 173 (using the immature marker doublecortin;Chaiton et al, 2018). Together with our findings, this 174…”

Neurobiological mechanisms underlying sex-related differences in stress-related disorders: Effects of neuroactive steroids on the hippocampus

“…These effects may be mediated via ER-dependent hippocampal actions, since bilateral injection of 17β-estradiol into the dorsal hippocampus has been shown to be anxiolytic ( Walf and Frye, 2006 ; Walf et al, 2006 ; Frye and Rhodes, 2002 ). However, altered hippocampal neurogenesis is not necessarily predictive for the behavioral outcome, as inhibition of estrogen synthesis via chronic letrozole treatment increases the number of immature neurons in the DG without affecting depressive-like behavior in middle-aged female mice ( Chaiton et al, 2019 ).…”