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Tuesday, September 22, 2015

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. 



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 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(!)



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 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, 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 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 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 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 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 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).


  1. Inhibit-P contains 300mg of vitex. Vitex is rumored to increase prolactin in low doses.
    PMS girls like this herb. Does that all mean that initially vitex has serotonergic effect, especially at 5ht2a receptor. But then its effect on dopaminergic neurons is much more powerful. It is said vitex lowers serotonin. Which way? This study ( says it doesn't influences mush on serotonin reuptake (but vitex was shown to increase serotonin standard metabolite measured in labs). And strange thing: I read 5ht2a can increase D2? Or it does that independently? If 5ht2a is supersensitive is it still prolactinergic?

    1. You also mentioned that low estradiol has correlation with upregulated 5ht1a. And study "Possible Modulation of the Anexiogenic Effects of Vitex Agnus-castus by the Serotonergic System." proposes vitex has synergy with 5ht1a autoreceptor antagonists.

      Are there any such graphs for vitex?
      Ashwagandha can increase prolactin in HIGH doses?
      Has effect on D2 (Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats.)///

    3. Serotonin causes appetite suppression (anorectic) effects by 1A, 2C, 4A in theory, Lysine, Agomelatine and WAY 100 635 should abolish the appetite suppressant effects of serotonin - my feeling is the 5-HT4 receptor is more potent than the 1A in this regard but less potent than the 2C. This is also consistent with serotonin's ability (perhaps opposite) to INCREASE histamine by the 4A receptor but decrease it by the 2A receptor....

    4. If 5-HT2A is ''supersensitive'' then you will have increase in Prolactin and Cortisol. But 5-HT2A is a tricky receptor, because if it is stimulated too much (by serotonin or others) then it ends up decreasing (downregulating).

      5-HT2A is a pro-emotional receptor, whereas 5-HT1A decreases emotions.

      Also, to go back to the appetite topic.

      5-HT4 receptors are interesting and totally unique, they increase Cognition and Memory, but they also increase stress in response to low food. So if you have less than adequate food supply and 5-HT4 is activated, you have more stress than someone with less activation of that receptor. 5-HT4 is also linked to primal aggression relating to food, as in battling the next person for food. So in poverty, serotonin probably plays a pro-aggressive role.


  2. As far as Vitex, I'm not sure how exactly it depletes serotonin levels but it could be due to it's selective interaction with brain endorphins/opioid peptides...some opioid receptors when activated decrease serotonin and others increase it.

  3. And for the 5-HT1A question - yes, that's true, low estrogen especially if combined with low cortisol amplifies the expression of 5-HT1A - this can be good or bad, depends on the person; it certainly leads to less serotonin release by a variety of pathways..but if your E2 levels are low I would recommend mildly increasing them (only if deficient) by using NMDA agonists like D-Aspartic Acid..also low E2 tends to create most of it's side effects by diminishing glutamate transmission so most of those issues come from the striatal membranes and GPCR's located there. Contrary to popular belief though, E2 isn't strictly 'needed' for male libido or sexual function - but it does contribute by said depends on the person - some people are very susceptible for even minor decreases in nitric oxide and such - and these types of people are likely to feel the 'crash and resolve' from even minor decreases in estrogen.

  4. Replies
    1. Progesterone regulates gamma-aminobutyric acid B (GABAB) receptors in the neocortex of female rats.

    2. Thanks for that study! I'll add it in soon. Also thanks for joining the forum; we need some bright minds around there. :)