Brain-selective estrogen therapy in male and female marmosets partially counteracts the adverse effects of aromatase inhibition on the brain and behavior

Blocking estrogen synthesis via aromatase inhibition helps prevent the recurrence of estrogen-receptor positive breast cancer but also results in cognitive, sleep and thermoregulatory disturbances. These side-effects diminish quality of life and contribute to treatment nonadherence in a large proportion of patients. DHED is a brain-selective prodrug that, in rodent models, converts to 17β-estradiol (E 2 ) selectively in the brain without affecting the periphery. We investigated whether DHED could prevent side effects associated with the aromatase inhibitor letrozole in a primate model of aging. Chronic oral treatment with DHED in letrozole-treated male and female marmosets led to a robust increase in E 2 levels across brain regions without affecting estrogen levels at the periphery. In addition, DHED treatment (1) improved memory at short delays and prevented letrozole-induced cognitive slowing in a hippocampal-dependent memory task; (2) normalized hippocampal neuronal membrane potential and excitability and (3) reduced sleep fragmentation. However, DHED treatment had opposite effects on thermoregulation in males and females, necessitating additional research in this area. Overall, the results suggest that DHED, which lacks estrogenic effects in peripheral tissues, could be a safe and effective novel hormonal therapy for improving quality of life in breast cancer patients treated with aromatase inhibitors. Significance statement Women with estrogen receptor positive (ER+) breast cancers take aromatase inhibitors to lower estrogens and reduce cancer recurrence. As a result, they often experience symptoms of estrogen deficiency that compromise treatment adherence. Here, we show that a brain-selective estrogen therapy administered orally via the prodrug DHED substantially increases estrogen levels in the marmoset brain without affecting the periphery and normalizes impairments in working memory, hippocampal neuronal excitability and sleep induced by aromatase inhibition. These findings in a translational primate model represent a significant advance for women’s health by positioning DHED as a non-invasive, safe and efficient novel hormone therapy to improve quality of life of women with ER+ breast cancers.