You say estren, I say estrogen. Let's call the whole replacement off!

Abstract

Estrogens and androgens play a key role in regulating bone mass. However, their clinical use as bone anabolic agents is limited due to unwanted side effects, particularly in reproductive organs. In 2002, the synthetic ligand estren was described to reproduce the bone anabolic, nongenotropic effects of sex steroids while having no effect on the uterus or seminal vesicles. But in the current issue of the JCI, Windahl et al. provide data showing that estrens are not as suitable a replacement for estrogen as was initially reported (see the related article beginning on page 2500). Though not catabolic, estrens triggered only minor, nonsignificant increases in bone mass in gonadectomized mice, all the while inducing hypertrophy of reproductive organs. Does this mean estrens should not be pursued as a therapy for osteoporosis?

Figure 1. Pathways of estrogen, SERM, and estren signaling.

In the genomic pathway of estrogen action (i), estrogen or SERMs bind to the ER, regulating transcription of target genes in the nucleus by binding to estrogen response element (ERE) regulatory sequences and by recruiting coregulatory proteins (CoRegs). Estrens were previously thought only to signal through the rapid, nongenomic pathway mediated by the ER located in or adjacent to the plasma membrane (ii), which may require the presence of adaptor proteins, which target the ER to the membrane. Activation of the membrane ER leads to a rapid change in cellular signaling molecules and stimulation of kinase activity, which in turn may affect transcription. Figure and legend adapted from ref. .