Work

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

Year: 2026

Type: article

Abstract: Menopausal hormone therapy (MHT), prescribed for climacteric symptoms including hot flushes and weight gain, contains estrogens such as 17 beta-estradiol (17βE2). However, estrogen receptor activation by MHT may increase reproductive cancers in some people. As the protective metabolic effects of 17βE2 are partly mediated through the arcuate nucleus (ARC) of the hypothalamus, restricting 17βE2 actions to the brain could serve as a safer method for MHT. The prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) is enzymatically converted into 17βE2 exclusively within the brain. DHED has already demonstrated positive benefit in rodent models of hot flushes and cognitive decline, while avoiding peripheral hormonal burden. Therefore, we hypothesized that DHED treatment in obese female mice would act within the hypothalamus to provide the same beneficial metabolic effects as 17βE2. Female mice were ovariectomized, placed on a high fat diet and split into control, 17βE2, or DHED treatment groups. Body weight, uterine weight, glucose tolerance and peripheral concentrations of luteinizing hormone were recorded, along with the expression of the progesterone receptor and kisspeptin mRNA within the ARC. Delivery of DHED at a similar dose as 17βE2 failed to improve metabolic parameters or recapitulate the hypothalamic responses induced by 17βE2. Our findings subsequently show that delivery of DHED at higher doses elicited estrogen-like actions within the brain but still failed to improve metabolic health. Additional investigations surrounding DHED's conversion to 17βE2 within the hypothalamus are warranted to conclude whether estradiol actions exclusively within the central nervous system can independently regulate protective effects on metabolism.

Source: Endocrinology

DOI: 10.1210/endocr/bqag082