The Third Bride; Explaining How Progesterone Works in the Brain (Progesterone Influences on Neurotransmitters/Synaptic Function)

This ladies and gentlemen is the third article of it's kind - first we had DHT and the brain, then we put out Estrogen's Impact on Brain Function - now we have the third, the tip of the iceberg. The point of the pyramid. You get it.

This article will step into the land of what would to some be - the never-before seen. 

Progesterone is often seen marketed as a one-stop solution to 'man-boobs' and a whole host of other ailments; a panacea if you will. Unfortunately, there isn't much to back up these claims and the studies that are around are either heavily biased or reported in questionable study environments. That doesn't mean however, that I am debunking Progesterone's usefulness. It just means I don't entertain the thought of it being promoted in such ways - especially given that the symptoms of high progesterone in men can be just as disturbing (if not more) than low progesterone.

With that being said, I have a job to do. 

Infor.Mation

PROGESTERONE AND THE BRAIN

Progesterone is involved in many central neurological pathways; it is heavily involved in nociception / anti-nociception (perception of pain) (1), transferring nerve impulses and regulating synaptic strength - in which are it's highlights(2). As well as maintaining and repairing myelin(3).

However, some of these pathways and functions it maintains may also be a result of endocrine interactions - in other words, interactions with other hormones(4)(5). Of key interest are Progesterone's effects on estrogen metabolism and bioactivity(6) (7).

Progesterone is shown to selectively modulate or regulate the activity of the eR (estrogen receptor) and also tends to decrease aromatase activities in the brain and endometrium(8)(9). The antagonistic profile of progesterone on estrogen-mediated responses though, is dose-dependent or concentration dependent(9). Moreover, Progesterone appears more significant in women than in men - in degree of potency and in regard to trafficking and hormone metabolism(10).  

For example, high progesterone could actually lead to over-inhibition of DHT (5-alpha-reductase) in men which could then lead to excessive estrogen receptor activity and subsequent gynecomastia in men(11)(12). In women however, progesterone seems to only be inhibitory to estrogenic effects - even in high concentrations. 

Additionally, Progesterone also has some differential effects between brain of man and woman(13).

Progesterone has diverse effects on glucocorticoids; it can reduce the stress-induced rise in cortisol levels - namely in situations of social stress(!). It may also increase ACTH levels and contribute to adrenal hyperplasia(14) (15).

Given all of these interactions it can be difficult to factor in the 'net' effect of Progesterone throughout. 

Though, there are many consistencies as well. 

PROGESTERONE AND GABA

Progesterone suppresses glutamic acid decarboxylase (GAD67) in the medial preoptic area; an area of the hypothalamus concerned with hormone production and sexual function/behavior(16).  Glutamic Acid Decarboxylase also known as simply glutamate decarboxylase; causes glutamate to CONVERT into GABA - as a result, PROGESTERONE effectively DECREASES the GABA level in this area of the brain(17)*. This leads to uninhibited cell firing , especially of glutamatergic neurons and subsequent increases in Gonadotropin. In theory, this could mean that Progesterone can improve fertility and sexual functions in moderate concentrations. 

This inhibitory (blocking,decreasing) effect of Progesterone on GABA activity also seems to extend to the amygdala (an area related to emotions and social interactions)(18). 

Progesterone's GABA-related effects in other area's of the brain are less clear; but it appears to be generally opposite to it's effects in the mPOA. It can produce a sedative effect (19) and increase GABA-A activity(20). These effects however seem to be primarily related to it's conversion into other metabolites(21). Taking all of the above into consideration, progesterone can certainly affect behavior to a degree - and it appears to be able to have anti-stress and anti-anxiety effects in low-moderate concentrations - whereas high levels may produce the opposite effect (especially in Men). 

Progesterone increases GABA-B receptor binding and affinity for ligands; meaning the more Progesterone - the more of an effect one would get from say, BACLOFEN(!). 

< Does PROGESTERONE CREAM INTERACT WITH / Baclofen? YES. >

PROGESTERONE AND HISTAMINE

Not much is known about specific steroid interactions with histamine, but progesterone appears to block or reduce the effects of histamine and DHEA-S induced histamine in regards to pain and may also reduce histamine release in the brain(22) (23) (24).


PROGESTERONE AND ACETYLCHOLINE
Progesterone appears to have anti-nicotinic effects; thus explaining it's proposed efficacy as a smoking cessation / anti-craving aid (25)(26) - it appears to do this by directly interfering with a specific docking site in which is shared by both progesterone and nicotinic neuronal networks(27).

Progesterone does not appear to influence any other parameter's of cholinergic function although it is postulated that it may influence (very mildly) the Ca2+ ignited glutamaterigc/cholinergic cell function(28). It is unable to ameliorate scopolamine induced memory deficits indicating it does not affect muscarinic activity(29).

PROGESTERONE AND SEROTONIN


Progesterone, like Estrogen, tends to increase Serotonin production; especially in the dorsal raphe nucleus; which is a brain region implicated in the pathyphysiology/development of depression. TPH2; Tryptophan Hydroxylase Type 2 is the enzyme that creates serotonin. Progesterone increases the activity of this enzyme - creating more serotonin(30) 
Because Progesterone markedly increases serotonin synthesis and bioactivity; one should take great caution in the simultaneous use of amphetamine derivatives and Progesterone as their interactions may result in a dangerous accumulation of serotonin and / or dopamine activity(31).

Progesterone seems to negate the effects of serotonin 1B/1D antagonists in some circumstances - such as restraint stress models (32) and it also may increase serotonin 2A receptors alike to estrogen's actions(33).

PROGESTERONE AND DOPAMINE

Progesterone is shown to decrease TYROSINE HYDROXYLASE which is the enzyme which leads to the creation of dopamine - but only initially; chronic administration of Progesterone or prolonged elevations tend to increase TH activity; leading to increased levels of dopamine and dopamine projections ; especially in the hypothalamus(34). Progesterone is also able to reverse estrogen-induced decline of TH - namely in the Arcuate Nucleus (35).

Thus, Progesterone (P) is able to increase dopamine neuron activity when reached at a stable and consistent level. Acutely though, it may have the opposite effect so one should expect any Progesterone treatment to not reach full benefit until at least 1.5 or 2 weeks in.


PROGESTERONE AND NORADRENALINE

Progesterone can directly interact with noradrenergic terminals to increase basal and electrically evoked NE/EPI secretion - this suggests a stimulatory effect - however, the net effect of Progesterone is actually inhibition due to evoking the increase in Monoamine Oxidase A - especially in the hypothalamus(36) (37) (38). The conclusions that can be made are that Progesterone may affect the periphery; such as uterine and corpus caversonum tissues by increase adrenaline-contractions - however, in regards to the NERVOUS SYSTEM - Progesterone appears to play the OPPOSITE role when taking into consideration the MAO-increasing effects of Progesterone. 

On the other hand, Progesterone + Moderate amounts of Estrogen may result in a net stimulatory effect - so therefore it depends on the ratio of Progesterone:Estrogen. In men with high DHT and high estrogen combined - or high estrogen combined with high progesterone and low DHT - the result in adrenaline-dominance and likely high blood pressure and erectile dysfunction.

On the other hand, high levels of Progesterone coupled with LOW estrogen would result in LESS sympathetic nervous system activity; again , due to Progesterone's inhibitory effects.



PROGESTERONE AND GLUTAMATE

Progesterone seems to exert neuroprotective effects and to reverse evoked increase of glutamate (thus averting neurotoxicity) (39) , since it also increases GABA-A activity - this represents a second mechanism by which Progesterone has diverse anti-glutamate properties (40) HOWEVER - Progesterone may be able to amplify the NMDA/AMPA induced LH-surge/release - which means that {P} can increase sex hormones that are induced by AMPA or NMDA - conclusively this means Progesterone is a region-selective glutamate modulator (41).

PROGESTERONE AND NMDA-GLUTAMATE COMPLEXES

Progesterone ITSELF (alone) does not affect NMDA receptor concentration in most brain regions tested but in combination with Estrogen it reduces NMDA receptors in the FRONTAL CORTEX ONLY (42) . Progesterone reduces DHEA's stimulatory effect on NMDA receptors but again, itself, alone, has no effect on the receptor complex in most common regions e.g hippocampus, striatum etc  (43) (44).

In the Pitutary Gland however, Progesterone may increase NMDA receptor mRNA levels; especially when combined with estradiol(45).


PROGESTERONE AND BETA-ENDORPHIN 

Progesterone does not alter beta-endorphin in ANY AREA EXCEPT the hypothalamus and pituitary gland - where it INCREASES beta-endorphin ; both the total levels and release  / function. Progesterone's HPTA inhibitory effects most likely relate to the beta-endorphin increases and any anti-sexual effects of Progesterone also likely have to do with beta-endorphin, at least in part. (46) (47).