Treatment with brain specific estrogen prodrug ameliorates cognitive effects of surgical menopause in mice

Menopause is an endocrine shift leading to increased vulnerability for cognitive impairment and dementia risk factors, in part due to loss of neuroprotective circulating estrogens. Systemic replacement of estrogen postmenopause has limitations, including risk for estrogen-sensitive cancers. A promising therapeutic approach therefore might be to deliver estrogen only to the brain. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in ovariectomized mice (a surgical menopause model). We treated mice with the prodrug 108,178-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 178-estradiol only in the brain. Young and middle-aged C57BL/6 J mice received ovariectomy and subcutaneous implant containing vehicle or DHED and underwent cognitive testing to assess memory after 1-3.5 months of treatment. Low and medium doses of DHED did not alter metabolic status in middle-aged mice. In both age groups, DHED treatment improved spatial memory in ovariectomized mice. Additional testing in middle-aged mice showed that DHED treatment improved working and recognition memory in ovariectomized mice. These results lay the foundation for future studies determining if this intervention is as efficacious in models of dementia with comorbid risk factors.