User:Camillebhr/sandbox

 Nervous system [edit]

Progesterone has many non-reproductive functions in the central nervous system (CNS) which can modulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury.

Progesterone, like pregnenolone and dehydroepiandrosterone (DHEA), belongs to an important group of endogenous steroids called neurosteroids. It can be metabolized within all parts of the central nervous system.[68]

Neurosteroids are neuromodulators, and are neuroprotective, neurogenic, and regulate neurotransmission and myelination.[69] The effects of progesterone as a neurosteroid are mediated predominantly through its interactions with nuclear progesterone receptors (cPRs), PRA and PRB receptors, and non-nuclear PRs, namely the mPRs and PGRMC1. Through the activation of these different types of receptors, progesterone can induce the regulation of gene expression, modulation of neurotransmitter systems, and activation of signaling cascades.

Progesterone binds to cPRs, which are located in many regions of the CNS, such as the hippocampus, cortex, hypothalamus, and cerebellum.

Estrogen and progesterone interact within the brain as estrogen has been found to promote the expression of PRs. Progesterone acts in concert with estrogen in the brain in order to be effective.

 Brain and Behavior [edit]

Progesterone and estrogen interactions have been found to have effects on cognitive function within the brain, specifically through the effects of these hormones on neuronal activity and synaptic connections within the hippocampus, the major center for memory and learning. Research using rat models observed that behavioural and cognitive deficits linked to loss of reproductive hormones can be overcome by progesterone replacement. In human research, it was found that cognitive function and memory can vary cyclically as a result of ovarian hormone fluctuations throughout the menstrual cycle.

 Brain damage [edit]

See also: Progesterone (medication) § Other uses

Previous studies have shown that progesterone supports the normal development of neurons in the brain, and that the hormone has a protective effect on damaged brain tissue. It has been observed in animal models that females have reduced susceptibility to traumatic brain injury and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen and progesterone in females.[70] Progesterone has also been considered as an anti-epileptic agent because of its ability to suppress seizures.

Proposed mechanism[edit]

The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma and hemorrhage.[71][72]

Damage incurred by traumatic brain injury is believed to be caused in part by mass depolarization leading to excitotoxicity. One way in which progesterone helps to alleviate some of this excitotoxicity is by blocking the voltage-dependent calcium channels that trigger neurotransmitter release.[73] It does so by manipulating the signaling pathways of transcription factors involved in this release. Another method for reducing the excitotoxicity is by up-regulating the GABAA, a widespread inhibitory neurotransmitter receptor.[74] This mechanism involves the binding of progesterone’s metabolic derivative, allopregnanolone, to GABAA receptors which causes an increase in inhibition, resulting in a reduction in the hyperexcitability of neurons. Progesterone is thought to inhibit seizures by reducing the excitability of neurons.

Progesterone has also been shown to prevent apoptosis in neurons, a common consequence of brain injury.[75] It does so by inhibiting enzymes involved in the apoptosis pathway specifically concerning the mitochondria, such as activated caspase 3 and cytochrome c.

Not only does progesterone help prevent further damage, it has also been shown to aid in neuroregeneration.[76] One of the serious effects of traumatic brain injury includes edema. Animal studies show that progesterone treatment leads to a decrease in edema levels by increasing the concentration of macrophages and microglia sent to the injured tissue.[73][77] This was observed in the form of reduced leakage from the blood brain barrier in secondary recovery in progesterone treated rats. In addition, progesterone was observed to have antioxidant properties, reducing the concentration of oxygen free radicals faster than without.[74] There is also evidence that the addition of progesterone can also help remyelinate damaged axons due to trauma, restoring some lost neural signal conduction.[74] Another way progesterone aids in regeneration includes increasing the circulation of endothelial progenitor cells in the brain.[78] This helps new vasculature to grow around scar tissue which helps repair the area of insult.