Targeting Estrogen to the Brain via the Prodrug DHED does not Protect Against Metabolic Dysfunction in Obese, OVX mice

Abstract Menopausal hormone therapy (MHT) is prescribed for climacteric symptoms including hot flushes and weight gain and contains estrogens such as 17 beta-estradiol (17βE2). However, estrogen receptor activation by MHT may increase reproductive cancers and cardiovascular event risk in some people. As the protective metabolic effects of 17βE2 are partly mediated through the arcuate nucleus of the hypothalamus, restricting 17βE2 actions to the brain could serve as a safer mechanism of MHT. 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) is a prodrug of 17βE2 which is enzymatically converted to the parent hormone exclusively within the brain. DHED has demonstrated positive benefit in rodent models of centrally-mediated maladies including hot flushes, depression and cognitive decline, without 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 either control, DHED, or 17βE2 treatment groups. Body weight, uterus weight and glucose tolerance were recorded along with gonadal hormone receptor expression in the brain. Delivery of DHED at a similar dose as 17βE2 failed to improve metabolic parameters or recapitulate the hypothalamic responses induced by 17βE2. Delivery of DHED at higher doses, which elicited estrogen-like actions within the brain, still failed to improve metabolic health. Our findings suggest that peripheral actions, in addition to hypothalamic targets, may be required to mediate 17βE2’s protective effects on metabolism and that brain-targeted MHT may be unsuitable for improving metabolic health during menopause.