On progesterone and allopregnanolone: effects on the central nervous system (CNS)

[Meso]

Here's my latest article on progesterone and allopregnanolone's effect on the brain and involvement in PSSD/PFS. Thanks for reading!

https://www.theresearchzone.com/post/on ... -the-brain

[Rb26dett]

I read about people that cured PFS using Ella pill. I don't know if ot's real or fake...

[naiverat]

Good work as always, meso - making a complex topic a bit more digestible and furthering our understanding of this condition.

I find it interesting how some of us have increased anxiety, lowered (or no) anxiety, or just baseline anxiety. How does this fit in with the insensitivity to allogrep? Since allopreg it's a positive allosteric modulator of GABA-A -- just like benzos -- shouldn't insensitivity to it increase our basal levels of anxiety (unless the "compensatory mechanism" decreases neuronal activity/firing in another manner)?

[Blueturtle]

Absolutely fantastic article mesolimbo, really helps to connect the dots with mood disorders, PSSD and PFS.

Keep up the great research it’s very informative.

[Meso]

Good work as always, meso - making a complex topic a bit more digestible and furthering our understanding of this condition.

I find it interesting how some of us have increased anxiety, lowered (or no) anxiety, or just baseline anxiety. How does this fit in with the insensitivity to allogrep? Since allopreg it's a positive allosteric modulator of GABA-A -- just like benzos -- shouldn't insensitivity to it increase our basal levels of anxiety (unless the "compensatory mechanism" decreases neuronal activity/firing in another manner)?

I think the altered anxiety response depends on several factors, allopregnanolone being only one of them. Antidepressants aren't equal when it comes to how much they increase Allopregnanolone. Paroxetine is more potent than Sertraline, for instance. Also, the mechanism of tolerance to allo isn't as simple as in benzodiazepine's, since several subunits of GABA-A receptors are involved. Allopregnanolone also doesn't merely act on GABA-A alone, there are several other effects, including facilitation of NMDA firing in the hippocampus, so the tolerance's mechanism is overall unclear.
https://www.ncbi.nlm.nih.gov/pubmed/22081320

Regarding anxiety, at low and moderate doses allopregnanolone increases amygdala reactivity. It only inhibits the amygdala at higher doses. It's a very complex substance. Keep in mind that I think only a partial insensitivity took place due to a compensatory mechanism. And depending on your level of allopregnanolone post-drug, it can explain some of the symptoms including feeling better during alcohol's hangover.

[Tree]

@Mesolimbo

"Allopregnanolone potentiates GABA-A mediated inhibition of 5-HT neurons in the dorsal raphe nucleus (DRN)"

Could gaba agonism indirectly upregulate 5ht1a receptors? At least in the short term

If so, wouldn't Allopregnanolone further enhance gaba induced 5ht1a upregulation temporarily?

[kamikaz3]

@Mesolimbo

"Allopregnanolone potentiates GABA-A mediated inhibition of 5-HT neurons in the dorsal raphe nucleus (DRN)"

Could gaba agonism indirectly upregulate 5ht1a receptors? At least in the short term

If so, wouldn't Allopregnanolone further enhance gaba induced 5ht1a upregulation temporarily?

Does this mean it inhibits the autoreceptors from firing? Or it potentiates the inhibitions of post synaptic 5ht neurons by activating the auto receptors (these are located in the DRN)

Confusing.

[lukejimmy]

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.
This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.

"Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons".
https://www.sciencedirect.com/science/a ... via%3Dihub
"Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators".
https://www.sciencedirect.com/science/a ... via%3Dihub
"Allopregnanolone and mood disorders".
https://www.sciencedirect.com/science/a ... via%3Dihub

This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.This seems to be a common effect of many GABAA receptor positive allosteric modulators.

"Pathogenesis in menstrual cycle-linked CNS disorders"
https://nyaspubs.onlinelibrary.wiley.co ... s.1286.005
"Allopregnanolone and mood disorders".
https://www.sciencedirect.com/science/a ... via%3Dihub

In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.

"Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone".
https://link.springer.com/article/10.10 ... 006-0417-0