Targeting estrogen to the brain via DHED does not seem to protect against metabolic dysfunction in obese OVX mice.

Preclinical animal study investigating the metabolic effects of a brain-targeting estrogen prodrug (DHED) in ovariectomized mice.

“We hypothesized that DHED treatment in obese female mice would act within the hypothalamus to provide the same beneficial metabolic effects as 17βE2.”

Ovariectomized female C57BL/6J mice placed on a high-fat diet.

“Female mice were ovariectomized, placed on a high fat diet and split into control, 17βE2, or DHED treatment groups.”

Approximately 6 to 7 mice per treatment group across three experiments.

“n = 6 for vehicle treatment, n = 7 for 5 μg/day 17βE2 treatment, n = 7 for 5 μg/day DHED treatment.”

Treatment periods ranged from 2 days (acute) to 25 days (chronic), following an initial 4-8 week high-fat diet period.

“Mice were then placed on a 45% HFD (SF04-001, 35.8% CHO, 18.5% PRO, 45% FAT) from Specialty Feeds (Glen Forrest, WA) for 8 weeks before being randomly assigned to 1 of 3 different hormone treatment groups.”

DHED treatment failed to improve body weight, food intake, or glucose tolerance compared to controls, unlike 17βE2 treatment.

“Delivery of DHED at a similar dose as 17βE2 failed to improve metabolic parameters or recapitulate the hypothalamic responses induced by 17βE2.”

The study did not measure 17βE2 levels directly due to assay specificity issues, and it did not assess all potential metabolic traits such as depot-specific adipose tissue changes.

“Unfortunately, it was not possible to measure 17βE2 in this study, with most commercially available ELISAs lacking sufficient specificity.”