Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease

Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized steroid receptor (SR) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.