Multiple nuclear receptor signaling pathways mediate the actions of synthetic progestins in target cells

Synthetic progestins are used clinically to treat a variety of women’s health issues. Although progestins are designed to signal through the progesterone receptor (PR) to elicit specific pharmacological effects, they can also variably bind to and influence the activity of other nuclear receptors within target tissues, particularly the androgen and glucocorticoid receptors and, in some cases, they regulate mineralocorticoid and estrogen receptors. This article reviews current knowledge on progestin cross-talk to nuclear receptors other than PR, their resultant effect on receptor function in different in vitro models and the potential consequences of this activity for breast, ovarian and endometrial cancer. The impact of cell and tissue context, assay type, steroid metabolism and hormonal milieu in determining progestin-mediated activity are also presented. Collectively this review highlights the complexity of progestin action and the need for consideration of multiple mechanisms that act in concert to influence their ultimate biological activity.

► Progestins are synthetic hormones designed to mimic the effects of progesterone.
► They are prescribed for a variety of women’s health issues.
► Progestins bind to multiple nuclear receptors, including PR, AR, GR, MR and ER.
► Progestins can have activating, null or anti-hormone effects on a given receptor.
► These actions have important implications for hormone-dependent cancers.