Progesterone: An Enigmatic Ligand for the Mineralocorticoid Receptor

Abstract

The progesterone receptor (PR) mediates progesterone regulation of female reproductive physiology, as well as gene transcription in non-reproductive tissues, such as brain, bone, lung and vasculature, in both women and men. An unusual property of progesterone is its high affinity for the mineralocorticoid receptor (MR), which regulates electrolyte transport in the kidney in humans and other terrestrial vertebrates. In humans, rats, alligators and frogs, progesterone antagonizes activation of the MR by aldosterone, the physiological mineralocorticoid in terrestrial vertebrates. In contrast, in elephant shark, ray-finned fishes and chickens, progesterone activates the MR. Interestingly, cartilaginous fishes and ray-finned fishes do not synthesize aldosterone, raising the question of which steroid(s) activate the MR in cartilaginous fishes and ray-finned fishes. The simpler synthesis of progesterone, compared to cortisol and other corticosteroids, makes progesterone a candidate physiological activator of the MR in elephant sharks and ray-finned fishes. Elephant shark and ray-finned fish MRs are expressed in diverse tissues, including heart, brain and lung, as well as, ovary and testis, two reproductive tissues that are targets for progesterone, which together suggests a multi-faceted physiological role for progesterone activation of the MR in elephant shark and ray-finned fish. The functional consequences of progesterone as an antagonist of some terrestrial vertebrate MRs and as an agonist of fish and chicken MRs are not fully understood. Indeed, little is known of physiological activities of progesterone via any vertebrate MR.

Serum Progesterone is Negatively Associated with Hypertension and Blood Pressure Indicators Among Men and Postmenopausal Women

“…Third, progesterone, which works by binding to progesterone receptors (PR), is a mineralocorticoid antagonist (MRA). According to clinical animal studies, it has a high affinity for MRA and can regulate electrolyte transport and promote normal metabolism of sodium and potassium ions in the kidneys of humans and other terrestrial vertebrates, thereby maintaining normal blood pressure 37 . MRA can improve blood flow mediated dilation, which is the mechanism of regulating vascular tension in hypertension 38 .…”