Sex‐dependent effects of letrozole on anxiety in middle‐aged rats

Abstract

Aromatase catalyzes the conversion of testosterone to estradiol and is involved in the physiological effects of sex hormones on brain function. Animal experiments have shown that the aromatase inhibitor, letrozole, can induce anxiety in young ovariectomized females that are used as a model of aging. Whether or not these effects would be similar in intact middle-aged animals is unknown. The aim of our study was to analyze the effects of letrozole on anxiety in middle-aged rats of both sexes. Fifteen month old male and female rats were treated daily with either letrozole or vehicle for 2 weeks. The elevated plus maze was used to test anxiety-like behaviour. Sex differences were found not only in plasma concentrations of testosterone but also in the effects of letrozole treatment on plasma testosterone (P<.05). The interaction between sex and treatment was also proven in locomotor activity (P<.05) and time spent in the open arms of the elevated plus maze (P<.05). Letrozole-treated male rats spent 95% less time in the open arms of the elevated plus maze than the control rats did (P<.05) suggesting an anxiogenic effect of aromatase inhibition. This difference was not found between letrozole-treated and vehicle-treated females. In contrast to previous experiments on young animals, letrozole seems to induce anxiety in male but not in female middle-aged rats. This sex-specific effect might be related to sex differences of oestrogen and androgen signalling in aging brains. These results should be taken into account in clinical applications of letrozole, especially in men.

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…Sex differences in the brain estradiol levels partially reflect the differences in plasma, but are largely determined by its local synthesis and metabolism (Caruso et al, 2013;Hojo and Kawato, 2018). Brain estradiol synthesis generates sex differences in neurogenesis, synaptic plasticity and behavior (Bowers et al, 2010;Bender et al, 2017;Borbélyová et al, 2017;Brocca and Garcia-Segura, 2018;Kokras et al, 2018;Shay et al, 2018;Brandt and Rune, 2019) and, as it has been discussed in Section 3, contributes to the activation of neuroprotective mechanisms after CNS injury.…”

Sexually Dimorphic Effects of Aromatase on Neurobehavioral Responses

“…Aromatase-specific whole-body knock-out (ArKO) mice (bred on the C57Bl6 background) have been developed that constitutively lack aromatase activity throughout all stages of development. This has been a useful animal model to discern the role of aromatase in physiology and behavior of both sexes ( Boon et al, 2010 ; Borbelyova et al, 2017 ). There are also 15 known cases of aromatase deficiency in humans (8 men, 7 women) ( Boon et al, 2010 ).…”

“…In adolescent males, AI can be used to correct short stature due to pubertal delay ( Wit et al, 2011 ). In sexually mature men, AI can be used to assist with low sperm count and motility, which often contributes to infertility ( Schlegel, 2012 ; Borbelyova et al, 2017 ). In later adulthood, males often experience a slow, but steady decline in serum T, thus increasing their ratio of E2 to T, which may result in enlarged or painful breasts in men ( Tan et al, 2014 ).…”

“…In later adulthood, males often experience a slow, but steady decline in serum T, thus increasing their ratio of E2 to T, which may result in enlarged or painful breasts in men ( Tan et al, 2014 ). This can be treated with an AI to reduce the amount of androgens being converted to E2 and ultimately increase serum T concentrations that naturally decline with age ( Tan et al, 2014 ; Borbelyova et al, 2017 ).…”

Aging mechanisms and intervention targets

“…Furthermore, tissue inhibitor of metalloproteinase 2 (TIMP2) enriched in human cord plasma, young mouse plasma, and young mouse hippocampi is found in the brain after systemic administration of the cord plasma and increases synaptic plasticity and hippocampal‐dependent cognition in aged mice; depletion of TIMP2 compromises the cognitive benefits conferred by cord plasma; and treatment of brain slices with TIMP2 antibody prevents long‐term potentiation, suggesting that TIMP2 in human cord plasma possesses plasticity‐enhancing effect for targeting aging‐associated hippocampal dysfunction . Since sex hormones play a significant role in brain aging, if the effect of cord plasma or TIMO2 might differ between male and female animals may require further investigation.…”