A Reason To Avoid Aromatase Inhibitors? Neurotrophic Effects of Estrogen

It is increasingly recognized that sex hormones, and in particular, estrogen/estradiol are endogenous neuroprotective and neurotrophic factors.

The pro-cognitive effects of estrogen are not restricted to women, and may explain some gender differences in stroke recovery. Estrogen has classically been understood as a “reproductive” hormone, which may have hindered recognition of its role in cognition and synaptic plasticity.

Given that the enzyme aromatase is responsible for the conversion of androgens (e..g, testosterone) to estrogens, it seems worth asking whether aromatase inhibition might adversely affect neuroplasticity.

The breadth of literature on the role of estrogen/estrogen derivatives in cognitive function is vast, ranging from studies in rodents demonstrating enhanced cognitive recovery in animals treated with 17b-estradiol to the interaction between menstrual cycle phase and cognition.

Remarkably, peak cognitive function in women corresponds with cyclic changes in circulating estrogen during the menstrual cycle.

Here are a few highlights from the literature:

• Consistently, removal of circulating estrogen by ovariectomy reduces the number of proliferating cells in the hippocampus, and subsequent administration of estradiol reverses this effect.¹
• The neuroprotective actions of estradiol have been studied extensively using various animal models of neurological disease, including kainic acid–induced excitotoxicity², cerebral contusion³, hypoxia⁴, amphetamine substitute analog-induced toxicity⁵, and cerebral ischemia
• Cerebral ischemia-induced brain injury and diffuse traumatic brain injury are reduced in female animals compared to males; removal of ovaries eliminates this protective effect.⁶
• Exogenous administration of estrogen robustly (and dose-dependently) reduces infarct volume after both focal and global cerebral ischemia.
• Elegant experiments where the aromatase gene is knocked out in animals results in a larger infarct size after brain injury; administration of aromtase inhibitors results in a similar pattern of increased post-ischemic cortical and striatal damage.⁷
• It has been documented that women are “protected” against stroke relative to men until menopause, when estrogen levels decline.⁸
• It has been proposed that selective nonsteroidal estrogen modulators (SERMS) may have therapeutic potential in the treatment of neurodegenerative disease.⁹
• Estrogen increases expression of the anti-apoptotic gene bcl-2 in an animal models ¹⁰ and also in vitro in rat hippocampal neurons ¹¹
• Estrogens suppress microglial activation and pro-inflammatory mediators that contribute to neurodegeneration.¹²
• Estrogen and estradiol attenuate damaging O2 radicals and H2O2 post-ischemia; estrogen itself actually has intrinsic free-radical scavenging activity by capturing hydroxyl radicals to form a nonphenolic quinol.
• Estrogen protects cerebral endothelial cells by increasing mitochondrial efficiency, promoting cell survival and angiogenesis, and suppressing ROS formation.¹²

Given all of the above, it might be time to ditch aromatase inhibitors altogether (unless you have constitutionally low testosterone).