For postmenopausal women or for women who have had surgery to remove their ovaries, estrogen replacement therapy can help smooth out hot flashes, depression, weight gain, and other side effects stemming from abnormal hormone levels. But taking an estrogen supplement doesn’t come without side effects, such as increased risk of breast and uterine cancer. Researchers led by Benita S. Katzenellenbogen and John A. Katzenellenbogen of the University of Illinois, Urbana-Champaign, have a possible solution with a set of “pathway preferential” estrogen analogs they have developed (Sci. Signal. 2016, DOI: 10.1126/scisignal.aad8170). When estrogens bind to estrogen receptors, they trigger a set of biochemical pathways. The extranuclear signaling pathway, which involves a transient estrogen binding process, helps control metabolism in adipose tissue and in the liver to reduce fat accumulation and repair blood vessels. The nuclear signaling pathway, which requires sustained estrogen binding, stimulates activity in reproductive and breast tissue, including the proliferation of cancer cells. The Katzenellenbogens and their team designed estrogen analogs, such as PaPE-1 (shown), that preserve the essential chemical features of estrogens but reduce estrogen receptor binding affinity. Working with mice, the researchers found that the analogs trigger the extranuclear pathway but don’t bind strongly enough to sustain the nuclear pathway, providing potentially trouble-free options for hormone replacement therapy.