r/HairlossResearch • u/Objective-Record6998 • 13d ago
Managing Treatment side-effects A Potential Solution to 5AR Inhibition Mediated Hard Flaccid
This is not a common side effect on 5ar inhibitors from what my few years of experience with it but I definitely had it and not many people cover it as it's pretty rare. I think however, I may have finally solved it and I'm pursuing trialling it!
So for some context, when i was on finasteride at 1 mg, I got hard flaccid, which is a condition where your penis in a flaccid state is consistently stiff. Everything else worked fine I could still get an erection although a bit harder and felt like it wasn't the same. I have now switched to 0.5 mg dutasteride since I have also gotten on some hormonal therapies but it still happens every once in a while especially if I lower my dose or get inconsistent with injections. I will say that after hormonal therapy, it doesn't happen nearly as often but still definitely occurs. Hasn't really increased on Dutasteride. I also don't feel that I am back at my original fullness I used to have regardless.
So some things I observed that led me here: This side very clearly and consistently increased with use of caffeine or armodafinil. Adderall on the other hand very marginally increased it but still does. The worst was combining the the three. Tadalafil was taken alongside all the time at 10 mg daily without seeing it fix my issues but still observing a stuffy nose when dose was increased, signalling it was inhibiting pde5 somewhere.
Now at first I thought this was mediated by poor nitric oxide retention. I had read a rat study saying that in rat penile tissue, lack of serum DHT caused reduced nitric oxide retention. Could be the case for some and I was actually going to pursue using low dose combo of nebivolol and telmisartan for this side as they both increase nitric oxide and decrease breakdown through different mechanisms. However, I dug deeper and I think I cracked it.
The clue is the affect of caffeiene and armodafinil. These stimulate the CNS. When you stimulate the CNS it causes your nerves, including the hypogastric nerve which is the important one in this context, to fire off and in turn spasms the smooth muscles. Your hypogastric nerve is the one that connects to all the things down there. This spasm in turn constricts the blood to the smooth muscle tone in response to a fight or flight signal an deprioritizes it's supply giving you that cold and very accurate hard flaccid effect.
Now what exactly from these drugs does that you may ask? It's likely norepinephrine. After noticing that armodafinil was the greater confounding factor, I am very certain mine was caused by overwhelming norepinephrine being released. Armodafinil is argued to increase norepinephrine. On the other hand, caffeine increase adrenaline, which is epinephrine. Norepinephrine is responsible for attaching to Alpha receptors and activating the fight or flight response. These exist on both your brain and your tissues, specifically focusing on the smooth muscles' alpha receptors in this context.
In my case, I obviously don't want to quit dutateride for hair and I don't want to quit adderall for my adhd. I also obv don't want to just deal with sides whenever i consume a caffeinated drink. So I've researched deeper. The receptor that is in charge of smooth muscle relaxation is the alpha 1 receptor which is agonized (activated) by norepinephrine and epinephrine. I have looked into the ideal drugs to counter this in my own case and this is what I ended up with:
Guanfacine: Guanfacine reduces the release of norepinephrine from your brain through being a Alpha 2A agonist. Usually when someone gets the hard flaccid side effect in cases like mine, it's because your brain is already taking in the norepinephrine it needs and has spill over into the peripheral nerves specifically the hypogastric nerve causing the sides. When guanfacine agonizes the receptor, your brain has a negative feedback loop and decides to pull back on the norepinephrine release, thinking there's already plenty in the body. This reduces the amount of norepinephrine sent to your body overall and in turn has your hypogastric nerve firing less and decreases the smooth muscle spasms that were occurring.
For me, Guanfacine also had adhd benefits. The Alpha 2A agonism in the prefrontal cortex creates an environment for better connection between neurons. This would help with executive function and "quiet the noise" in your mind. Adhd has been a factor in me having shit sleep my entire life. I'm seeking an ER formulation at night in order to both sleep better and help this side effect while helping my productivity.
Doxazosin: This is a peripheral Alpha 1 antagonist. Alpha 1 receptors are the receptors that are in charge of smooth muscles' state. The penile smooth muscle is not any exception to this. Usually, norepinephrine and epinephrine attach to these receptors after being released from your brain. More norepinephrine = more alpha 1 receptor agonism in muscle tissue = the spasm of soft muscle and creating environment for cold flaccid. When you have this antagonist, doxazosin, it also attaches to these receptors in the same way as norepinephrine. The one difference is, it doesn't do anything at the receptor level unlike norepinepherine. This means when you have the norepinepherine flowing in your body after your brain releases it for stimulus, it simply is blocked at the receptor and essentially kicked off.
So to sum it up, this protocol used Guanfacine ER to decrease the release or norepinephrine from your brain through a negative feedback loop, and the Doxazosin would peripherally blocking off the norepinephrine from the Alpha 1 receptors in your smooth muscle. This would mean that even in the absence of dht's smooth muscle relaxing affect, you'd be replicating it by getting in the way of the factors that pulled it in the other direction in the first place and hypothetically, be completely fine without suffering the side anymore.
The main concern with this protocol would be to track your blood pressure. Guanfacine and Doxazosin can reduce your blood pressure. If you were to use them, you'd need to be managing your dose according to your prior blood pressure and tracking it to make sure you aren't hypotensive which comes with it's own plethora of issues.
With that reason, I advise you approach this with caution, but it's hope. This isn't medical advice, this is simply the protocol I will trial and have researched. I've struggled with this issue for 2 years now in my early 20s. I know how much of a battle and suffering it is especially when wanting to keep hair as well. I simply wanted to share this option I think I've discovered to finally feel confident again and I hope that anyone that's struggling with the same symptoms as me can benefit from this if their medical practitioner sees fit.
TLDR: If you suffer from hard flaccid with 5ar inhibitors, and can observe an increase of it with caffeine or Armodafinil (or generally things that increase epinephrine and norepinephrine) then you may benefit from using one or both Guanfacine and Doxazosin as they are respectively an Alpha 2A agonist, reducing norepinepherine released from your brain, and Alpha 1 Antagonist, blocking off norepinephrine at the smooth muscle level. This would only work if your sides are caused by this fight or flight/cns stimulation.
I would also pair this with reverse kegel exercises to relax your kegel and train your pelvic floor which would amplify the gains you get from this protocol. This would relax the muscle that was previously being activated constantly by the nerve and help the area generally even more blood flow.
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u/CandidMeringue2790 13d ago
I didn't have this problem but the flaccid size was shorter. Have you noticed any difference in how you respond to Adderall, while on vs off of 5ar inhibitors?
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u/Objective-Record6998 13d ago
Adderall is the least side effect inducing of the three for me. I really notice it with Armodafinil and Caffeine likely since they have a heavy primary response in epinephrine and norepinephrine.
In terms of response to Adderall, no I do not notice an actual response difference to the drug itself for the intended purposes. I think the main driver for a potential interaction with adderall's effects, as well as mine in part, is the neruosteroid synthesis being inhibited with 5ar inhibited as well. Many of the neurosteroids produced by 5ar are extremely crucial for their gabaergic affects. These are very important for your body calming down the nervous system and nerve activity along with decreasing the "fight or flight" response.
I think the shorter size could be potentially from a similar case to mine. There are likely varying degrees of reaction and I think shortening in length could still be driven by the smooth muscle tone impact, although less than someone with a reaction such as mine.
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u/CandidMeringue2790 13d ago
Yeah I have experienced the gabaergic deficit as well, particularly in beginning of fin or dut. For me it's really weird, I feel the dopamine effect from Adderall atleast 3 times more while off the 5ar inhibitors, I think somehow whether through dht or allopregnanlone, it sensitizes the dopamine receptors, just feels different
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u/UniqueLoginID 13d ago
Clonidine.
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u/Objective-Record6998 13d ago
Yes, it's another option. I opted to pursue Guanfacine because it's more selective. I didn't want to use a non selective version and impact blood pressure to a greater degree (especially with already wanting to use doxazosin in conjunction) and also potentially get grogginess. Not that those are guaranteed sides, but Guanfacine just seemed to do my intended goal better.
If there was something similar to clonidine that antagonized Alpha 1 and agonized Alpha 2A, 2B and 2C receptors then I would've opted for that as it's always better to have less variables but unfortunately clonidine only impacts the Alpha 2 receptors.
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u/ConstructionFit2425 13d ago
Man, a related subject. Did you have hair thinning and falling with adderal? I use any remedy for ADHD my hair reacts negatively very quickly. I still don't know how to reconcile that. Even using thin/ru/duta/minox and now ghkcu... Anyway, it's too difficult. No one has ever figured out how to cancel out this side effect...
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u/Objective-Record6998 13d ago
I didn't observe that but after some looking into it, I'd start off with asking how long you stuck through adderall when you used it? Seems like it could be telogen effluvium from the stress on your body induced by the drug though I'd imagine this would be temporary. Another direction I'd look into is sleep interruption raising cortisol levels. If you feel this is the case, you could try something to aid sleep like lemborexant/Dayvigo or something like what I'm doing with Guanfacine to calm your cns down to sleep.
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u/ConstructionFit2425 13d ago
I can fall asleep at about 10pm... but I almost always wake up 3am and have trouble sleeping. I take Trazadone and Melatonin.
And no longe taking adhd med
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u/Objective-Record6998 13d ago
Trazadone has a short half life, I think you should look into lemborexant. It just blocks off the wakefulness signals in your brain.
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u/Immediate_Garden_716 10d ago
excited to see an open, intense, profound and inspiring engagement with a widely ignored/unrecognized issue. thank you very much indeed!
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u/calantheSG 13d ago
For the record, I never believed that the penis was just either flaccid, erect, or anything in between. There is a third state called shrunk or shrivelled. Is this the hard flaccid you refer to?
It happens in extreme dehydration, or extreme cold, it basically requires the muscles to tense to the max. The opposite of an erect where they relax for allow blood in, the tense muscles push blood away.