Metabolic Effects of 17a-Estradiol are Growth Hormone Independent and Sex Specific

Aging is a major risk factor for metabolic syndromes and type two diabetes. With growing elderly populations worldwide and increasing incidence of age-related diseases there is a great need to develop pharmacological interventions that would delay aging and protect from age-related diseases. 17-alpha estradiol (17α-E2) is an epimer of the primary female sex hormone estradiol and has been shown to extend lifespan and downregulate markers of age-related metabolic dysfunction in male mice. Because 17α-E2 does not induce feminization in males it holds potential as a novel therapeutic in humans for age-related metabolic dysfunction. Importantly, we have previously shown that 17α-E2 causes an increase of circulating and hepatic IGF-1 in aged mice, without any changes in GH release in treated animals. Based on this we propose a new hypothesis that 17α-E2 acts through a novel, GH-independent pathway stimulating production of IGF-1 and positively modulating metabolic function in a sex-specific manner. Here we studied 17α-E2 treated long-lived growth hormone receptor knockout (GHRKO) mice, characterized by severely reduced circulating and hepatic IGF-1 due to GH-resistance. We found increases in circulating IGF-1 after treatment in normal and GHRKO male mice, with no effect in female mice, which supports our hypothesis that 17α-E2 induces GH independent IGF-1 production. To determine novel genetic pathways activated by 17α-E2 we performed sequencing of hepatic RNA. Our analysis indicated differential regulation of steroid biosynthesis and insulin signaling pathways. The validation of our sequencing data using qPCR showed significant upregulation of genes involved in insulin action. Importantly, differential regulation of these pathways was present in normal male mice, with no changes in normal females or either male or female GHRKO animals. In summary, this new data supports our hypothesis of a sex-specific effect of 17α-E2 treatment and differing mechanisms of action by which 17α-E2 upregulates IGF-1 independently of GH action.