17α-Estradiol: A mildly feminizing estrogen with sex-specific metabolic and lifespan benefits.

Estrogens are pleiotropic hormones that regulate reproductive and non-reproductive physiological processes in both sexes. Among these, 17α-estradiol (17α-E2), a C17 epimer of the canonical estrogen 17β-estradiol (17β-E2), has emerged as a promising modulator of aging and metabolism with sexual dimorphism. Unlike 17β-E2, which exerts broad estrogenic effects in both sexes, 17α-E2 extends lifespan and preferentially improves metabolic homeostasis in male mice while inducing only mild feminizing effects. Many of these benefits are mediated through estrogen receptor alpha (ERα). However, it remains unknown if its biological actions are mediated through genomic or nongenomic pathways and what the molecular basis is for male-biased efficacy. This review outlines evidence from preclinical models and translational studies, demonstrating that 17α-E2 mitigates age-related metabolic declines in males by reducing adiposity, enhancing insulin sensitivity, and preserving hepatic metabolic plasticity. Elucidating the sexually divergent actions of 17α-E2 can advance our understanding of sex-biased endocrine signaling and how these pathways modulate aging in a sex-specific manner.