3α-Hydroxysteroid dehydrogenase (3α-HSD) -- levonorgestrel?

[Meso]

So, I'm currently trialing Donepezil with some success for PSSD. But I've been suspecting something for a while: ever since I developed PSSD, I lost my response to nicotine and smoking, quite abruptly too.

I read that Venlafaxine (my poison) upregulates 3-HSD expression. This results in higher progesterone synthesis. Progesterone has antinicotinic effect through negative modulation and is being investigated as an anti-craving aid for smoking cessation. It also desensitizes estrogen receptors, so probably contributes to blunted affect as well.

Progesterone is one of few hormones that I haven't tested (not available to me), but I'm suspecting that I have a high level now. Perhaps Donepezil's benefits I'm noticing are due to activation of nicotinic receptors that are suppressed by progesterone?

I don't have access to ulipristal acetate (Ella), but I can get Levonorgestrel.
My question: Can low dose Levonorgestrel (0.03 mg), a progestin, cause a shutdown of endogenous progesterone synthesis through a negative feedback mechanism? Is it worth a shot?

[Jaxx]

id be very careful. levonorgestrel gave me immediate shrinkage, low libido and cortisol responds (or at least an energy surge). took me a small week to recover. i took 1/6 of a pill

[Meso]

id be very careful. levonorgestrel gave me immediate shrinkage, low libido and cortisol responds (or at least an energy surge). took me a small week to recover. i took 1/6 of a pill

Do you think low dose progesterone cream would be more appropriate to achieving this goal?

Any way to downregulate progesterone receptors or 3α-HSD expression?

[Jaxx]

havent seen much lasting effect with prog or ella for pssd but you could try. prog cream was good for morning wood in my case. ella is otc here, bit surprised its difficult to get.

[Jaxx]

After reading your progress in the Donezepil thread, id say stick with that for at least a month. Progesterone could send you back entirely, so why risk it at this point?

[Meso]

After reading your progress in the Donezepil thread, id say stick with that for at least a month. Progesterone could send you back entirely, so why risk it at this point?

It's just a backup plan. I'm using my newfound mental clarity to research PSSD's elusive etiology so I can come up with a plan now in case I lose said mental clarity due to i.e. tolerance to Donepezil's effect. I'm not going to trial progesterone now.

[Ciprofloxacin]

NSAIDs can inibit 3a-HSD. Ibuprofen, indomethacin etc.

https://forum.propeciahelp.com/t/maybe- ... ment/31409
https://forum.propeciahelp.com/t/ibuprofen-use/1470

Aldo Keto Reductase 1C Type 2:

Inhibited by hexestrol with an IC50 of 2.8 µM, 1,10-phenanthroline with an IC50 of 2100 µM, 1,7-phenanthroline with an IC50 of 1500 µM, flufenamic acid with an IC50 of 0.9 µM, indomethacin with an IC50 of 75 µM, ibuprofen with an IC50 of 6.9 µM, lithocholic acid with an IC50 of 0.07 µM, ursodeoxycholic acid with an IC50 of 0.08 µM and chenodeoxycholic acid with an IC50 of 0.13 µM.

Aldo Keto Reductase 1C Type 3:

Strongly inhibited by nonsteroidal anti-inflammatory drugs (NSAID) including flufenamic acid and indomethacin. Also inhibited by the flavinoid, rutin, and by selective serotonin inhibitors (SSRIs).

It’s bit complex though. 3a-HSD activity is decreases by long-term usage and increases by short-term usage. Also I think you should look to oxidative(reverse) pathway of this enzyme too.

3a-HSD activity has been described in the cytosolic and microsomal fractions of a number of human and animal tissues.17,19–25 To date, at least four types of cytosolic 3a-HSDs have been identified in humans (also called AKR1C1–AKR1C4), which display 3-, 17-, and 20-ketosteroid reductase activity. All of these cytosolic enzymes exhibit a preference for the phosphorylated nucleotides as cofactors (NADP þ, NADPH).26–28 AKR1C1 (in particular, 20a-HSD activ- ity and only weak 3a-HSD activity) and predomi- nantly AKR1C2 (3a-HSD type 3) are the only enzymes out of the aldo-keto reductase (AKR) superfamily with 3-ketosteroid reductase activity in humans, which are expressed in the CNS in a relevant amount.27,28 In contrast to cytosolic 3a-HSDs, microsomal enzymes with 3a-HSD activity strongly prefer NAD þ /NADH as cofactors.28–30 The predominant forms of nucleotide cofactors in the cells are NADþ and NADPH.28,31–33 Although both cytosolic and microsomal 3a-HSDs in principle can act bidirectionally in vitro, in the living brain, cytosolic 3a-HSDs are expected to almost exclusively catalyze the reductive pathway (conver- sion of 5a-DHP into 3a,5a-THP; cofactor: NADPH) whereas microsomal 3a-HSDs are expected to catalyze the oxidation of 3a,5a-THP into 5a-DHP (cofactor: NAD þ ), owing to the intracellular availability of the respective cofactors

If you think that 3a-HSD is problem, you also should consider the GABA signalling. Allopregnanolone is one of the strongest GABA activator and the ‘only’ way to inhibiting it is the GAMSAs

https://core.ac.uk/download/pdf/82767411.pdf

[Meso]

have u also lost ur ability to get drunk or high?

Yes.

NSAIDs can inibit 3a-HSD. Ibuprofen, indomethacin etc.

Very interesting.

[Meso]

Cipro, excessive daytime hypersomnolence has (had?) been a hallmark of my PSSD. Extremely flattened affect, too. In fact, one of the few only windows I got to feeling emotions pre-Donepezil was during a Clomiphene trial without an aromatase inhibitor (raising estrogen), but after a couple of weeks I lost my emotions again (probably through estrogen receptor mediated progesterone induction.)

I really do believe that at least Venlafaxine's main chemical castrating effect is mediated through progesterone via its 3-hydroxysteroid dehydrogenase upregulation, raising progesterone and allopregnanolone (positive GABA receptor modulator).

That aside, I read that Finasteride alters alpha-5 reductase expression/function, causing permanent:
1- Decreased testosterone -> DHT conversion.
2- Decreased progesterone metabolism.

It must be a really vile drug. But wouldn't that mean 5-alpha reductase induction would help me and those suffering from post finasteride syndrome?

[Meso]

I've researched 3beta-HSD inhibitors a little, to find easily accessible ones, and there are 4 good ones: daidzein, genistein, biochanin A and formononetin (all found in soybeans).

If an issue is largely progestronic in nature, without the involvement of low testosterone, then a phytoestrogen like soybean should be okay.

https://www.ncbi.nlm.nih.gov/pubmed/7488041

Dietary estrogenic isoflavones are potent inhibitors of beta-hydroxysteroid dehydrogenase. The isoflavones daidzein, genistein, biochanin A and formononetin selectively inhibit the gamma-isozymes of mammalian alcohol dehydrogenase (ADH). Since gamma-ADH is the only ADH isoform that catalyzes 3 beta-hydroxysteroid oxidation, it was conjectured that these isoflavones might also inhibit other enzymes involved in 3 beta-hydroxysteroid metabolism.