Rodent Models of Non-classical Progesterone Action Regulating Ovulation

Abstract

It is becoming clear that steroid hormones act not only by binding to nuclear receptors that associate with specific response elements in the nucleus but also by binding to receptors on the cell membrane. In this newly discovered manner, steroid hormones can initiate intracellular signaling cascades which elicit rapid effects such as release of internal calcium stores and activation of kinases. We have learned much about the translocation and signaling of steroid hormone receptors from investigations into estrogen receptor α, which can be trafficked to, and signal from, the cell membrane. It is now clear that progesterone (P4) can also elicit effects that cannot be exclusively explained by transcriptional changes. Similar to E2 and its receptors, P4 can initiate signaling at the cell membrane, both through progesterone receptor and via a host of newly discovered membrane receptors (e.g., membrane progesterone receptors, progesterone receptor membrane components). This review discusses the parallels between neurotransmitter-like E2 action and the more recently investigated non-classical P4 signaling, in the context of reproductive behaviors in the rodent.

“Rapid actions of the neurosteroid allopregnanolone on ovarian and hypothalamic steroidogenesis: Central and peripheral modulation”

“…Neurosteroids can bind to intracellular receptors, which are responsible for the classical genomic actions . They can also produce rapid effects (non‐genomic mechanisms) via ligand‐gated channels, such as GABA A and several other membrane receptors . The former have a response time in the order of minutes, hours or days, whereas the latter are faster (seconds to minutes) .…”

“…The time required to initiate this effect is rather protracted compared to the effect obtained with membrane receptors. Moreover, the seven‐transmembrane progesterone adiponectin Q receptors (PAQR/membrane P 4 receptors, mPRs) and finally, progesterone receptor membrane components are associated with the “non‐classical” rapid cell surface‐initiated action by promoting intracellular signalling cascades …”

“…There is ample evidence that the hypothalamus is exquisitely sensitive to gonadal steroids, which control neuroendocrine functions via non‐genomic mechanisms . Specifically, P 4 elicits acute effects via allosteric modulation of the GABA A receptor.…”

“…The mechanisms of action of neurosteroids classically involve two kinds of responses: (i) via membrane or surface effects (fast response) that usually work via modulation of ion‐channel receptors and (ii) via cytosolic receptors (slow response), activating traditional genomic expression . Rapid membrane‐initiated signalling of steroid hormones can affect neuronal responsivity and alter physiological processes such as neuroprotection and reproduction …”

Understanding the role of steroids in typical and atypical brain development: Advantages of using a “brain in a dish” approach

“…A possible cellular mechanism for the role of progesterone as a memory enhancer is its ability to provide neuroprotection against oxidative stress in the hippocampus, by down‐regulating pro‐apoptotic markers and up‐regulating anti‐apoptotic markers . Some studies suggest that progesterone‐mediated neuroprotection might be result of rapid membrane‐initiated kinase activity, which down‐regulates pro‐apoptotic factors such as Bcl2‐associated death promoter and up‐regulates anti‐apoptotic factor Bcl2, and this pathway is triggered via a membrane progesterone receptor . Although the effect of progesterone on the brain can be two‐pronged, depending on the timing and dose of the hormone, in some conditions, controlled doses of progesterone has been beneficial in ameliorating neurological symptoms, as also discussed later below.…”