Progesterone Actions During Central Nervous System Development

Abstract

Although progesterone is a steroid hormone mainly associated with female reproductive functions, such as uterine receptivity and maintenance of pregnancy, accumulating data have shown its physiological actions to extend to several non-reproductive functions in the central nervous system (CNS) both in males and females. In fact, progesterone is de novo synthesized in specific brain regions by neurons and glial cells and is involved in the regulation of various molecular and cellular processes underlying myelination, neuroprotection, neuromodulation, learning and memory, and mood. Furthermore, progesterone has been reported to be implicated in critical developmental events, such as cell differentiation and neural circuits formation. This view is supported by the increase in progesterone synthesis observed during pregnancy in both the placenta and the fetal brain. In the present review, we will focus on progesterone actions during CNS development.

Keywords: brain sex differentiation; brain tumors; myelination; neurodevelopment; neuroprotection; progesterone; progesterone receptor.

FIGURE 1

Sources of progesterone for the developing CNS. Progesterone synthesis begins with the conversion of cholesterol into pregnenolone by the cytochrome P450scc, which is in turn converted into progesterone by the 3β-HSD enzyme. Thereafter, the 5α-reductase enzyme can metabolize progesterone to 5α-dihydroprogesterone, which is further reduced to allopregnanolone. Progesterone synthesized by the placenta (ovaries in rodents) during pregnancy crosses the placental barrier, enters the fetal circulation and reaches the developing CNS. However, the fetal adrenal glands and CNS are also locations in which progesterone is synthesized and metabolized during the prenatal life.

FIGURE 2

Mechanism of progesterone actions. Progesterone exerts its effects on its target cells through two central pathways, namely the classical and non-classical ones. In the classical pathway, progesterone binds to its intracellular receptor (PR), activating such a transcription factor which dimerizes and translocates to the nucleus. There, it binds to specific DNA sequences, called progesterone response elements (PRE), which are mainly located in the gene promoter regions, thus regulating their expression. In contrast, the non-classical pathway involves the PR ligand-independent activation by membrane-associated kinases and the activation of multiple G protein-coupled membrane receptors of progesterone (mPRs), which in turn activates pathways related to cAMP-dependent protein kinase A (PKA), Ca²⁺-dependent protein kinase C (PKC), PI3K/Akt and ERK/MAPK. Furthermore, the non-classical action of progesterone includes the modulation of the γ-aminobutyric acid type A (GABA-A) receptors following its conversion into allopregnanolone.

FIGURE 3

CNS development events associated with the progesterone actions. The arrow of time represents the CNS development course during prenatal and early postnatal life, as well as some of the events associated with the progesterone actions occurring as the neurodevelopment proceeds. These actions include proliferation and differentiation of neural progenitor cells during prenatal neurogenesis, the maturation of oligodendrocytes and myelination before and after birth, neuroprotection before and after birth, sexual differentiation of the brain right before and shortly after birth, as well as the maturation of neural circuits in the late stages of pregnancy and during the first postnatal days.