Absence of Adverse Reactions When PDE5's Lose Efficacy

[Mazzio]

Pills do not lose their effect. Your ED is just getting worse.

[Cozpgh]

I agree with you that performance anxiety is most probably overriding the effect that PDE5i are having. Sympathetic influence can be all powerful in the penis, hence why Trimix injections work best as they deliver phentolamine directly to the penis and supress the inhibitive influence, the other two ingredients are strong direct relaxers of smooth muscle in the erectile tissues which by pass the NO pathway, the pathway PDE5i affect.
I also think that TRT can in many men exacerbate the influence of the inhibitive sympathetic pathway in the penis and sometimes in the whole body. I feel this is due to the way testosterone is delivered into the body artificially, it does not mimic the way we produce it naturally. The other issue with TRT is that is shuts down most of the upstream hormones with regard to testicular function and this can have far reaching effects on sexual function, specifically the loss of LH, FSH and GNRH. The ill effects of this take time to be felt. Are you at least using HCG in your protocol? This can for some men help to replace a portion of this in a crude manner. Taking more testosterone in order to try and combat this loss of upstream hormones usually only causes more problems with excessive E2, desensitisation of the androgen receptors and further increase in sympathetic function in the body. TRT can cause ED if the dose is too high. The loss of LH can cause anxiety to develop in many men. This anxiety can interfere with erectile function as well.

I now think that it is possible that PDE5i do lose effectiveness over time, I was opposed to this possibility, but if one utilises high doses of these drugs frequently, and these effects are changing how the enzyme PDE5 is working in the body, it make sense that the body may upregulate this enzyme over time to correct what it sees as a malfunction at a cellular level.

Wow. Thank you so much for such a well thought out response. I started the .25 Testosterone Cypionate w/ anastrozole twice weekly shortly after my divorce. While I'm sure the performance anxiety picked up being newly single and having new sexual encounters for the first time in 18 years, I've noticed a gradual worsening and more failures - even with combinations of high dose PDE5s - sometimes even with Trimix added in if I miss the mark injecting - the longer I've been on the TRT. I'm really not feeling any of the perceived benefits of TRT at this point. I'm still slow to recover from workouts, still have disrupted sleep, still have lulls in libido and ED issues, and still achy with focus issues. But my numbers and labs are really good. You just think I'd be feeling as good as the numbers.

Do you have a information source when it comes to your theory about TRT exacerbating the inhibitive sympathetic pathway? I' did a quick Google search and found this - https://www.swintegrativemedicine.com/b ... s-cause-ed - which speaks to the cortisol spike if testosterone is too high possibly attributing to ED. I mentioned the HCG to my doctor and he tried to ween me toward peptides instead. Didn't quite understand that. He told me that unless I was worried about the size of my testicles or trying to have kids he felt adding HCG to the TRT was more risk than benefit and wanted me to add .5 to my weekly TRT injections for a month prior to my next lab.

Despite the increased performance anxiety and addition of the TRT, I do feel something changed in how my body absorbs and responds to PDE5s. Like I said, for almost two decades, 25mg of Sildenafil with the occasional titration up to 50mg worked wonders for me. Instant facial flush, stuffy nose, spontaneous erections, a good hard on throughout sex. As i mentioned, I could lick just a droplet of crushed Sildenafil powder and get the facial flush. Often all of that within 30 minutes. I can take 200mg of Sildenafil now and have none of those side effects. I can still get a nice erection but maintaining it throughout intercourse has become difficult as has ejaculating. And there can be random spontaneous erections even 4 to 6 hours after dosing or hours after not succeeding with or finishing intercourse. I know the general consensus is the pills don't lose effect, your ED worsens over time, and I'm sure there's truth in the your ED worsens part. However, in my case, it has to be something with how my body is metabolizing the meds since the always customary side effects vanished even with higher doses (with the exception of heartburn at the end of the night) or my body up upregulating the enzyme in response to using the meds for so long. It's also not a matter of just switching up PDE5 inhibitors as they all require higher than recommended doses for the best result.

[slipnslider]

For me, pills lost effect over time, but the shitty side effects continued or even got worse. I wasn't willing to up the dosage to the level I'd need for a reliable erection, because the side effects would have been unbearable.

Injections have been a blessing. I love putting the drug right where its needed and leaving the rest of my body alone.

[Fourtytwo00]

I agree with you that performance anxiety is most probably overriding the effect that PDE5i are having. Sympathetic influence can be all powerful in the penis, hence why Trimix injections work best as they deliver phentolamine directly to the penis and supress the inhibitive influence, the other two ingredients are strong direct relaxers of smooth muscle in the erectile tissues which by pass the NO pathway, the pathway PDE5i affect.
I also think that TRT can in many men exacerbate the influence of the inhibitive sympathetic pathway in the penis and sometimes in the whole body. I feel this is due to the way testosterone is delivered into the body artificially, it does not mimic the way we produce it naturally. The other issue with TRT is that is shuts down most of the upstream hormones with regard to testicular function and this can have far reaching effects on sexual function, specifically the loss of LH, FSH and GNRH. The ill effects of this take time to be felt. Are you at least using HCG in your protocol? This can for some men help to replace a portion of this in a crude manner. Taking more testosterone in order to try and combat this loss of upstream hormones usually only causes more problems with excessive E2, desensitisation of the androgen receptors and further increase in sympathetic function in the body. TRT can cause ED if the dose is too high. The loss of LH can cause anxiety to develop in many men. This anxiety can interfere with erectile function as well.

I now think that it is possible that PDE5i do lose effectiveness over time, I was opposed to this possibility, but if one utilises high doses of these drugs frequently, and these effects are changing how the enzyme PDE5 is working in the body, it make sense that the body may upregulate this enzyme over time to correct what it sees as a malfunction at a cellular level.

Wow. Thank you so much for such a well thought out response. I started the .25 Testosterone Cypionate w/ anastrozole twice weekly shortly after my divorce. While I'm sure the performance anxiety picked up being newly single and having new sexual encounters for the first time in 18 years, I've noticed a gradual worsening and more failures - even with combinations of high dose PDE5s - sometimes even with Trimix added in if I miss the mark injecting - the longer I've been on the TRT. I'm really not feeling any of the perceived benefits of TRT at this point. I'm still slow to recover from workouts, still have disrupted sleep, still have lulls in libido and ED issues, and still achy with focus issues. But my numbers and labs are really good. You just think I'd be feeling as good as the numbers.

Do you have a information source when it comes to your theory about TRT exacerbating the inhibitive sympathetic pathway? I' did a quick Google search and found this - https://www.swintegrativemedicine.com/b ... s-cause-ed - which speaks to the cortisol spike if testosterone is too high possibly attributing to ED. I mentioned the HCG to my doctor and he tried to ween me toward peptides instead. Didn't quite understand that. He told me that unless I was worried about the size of my testicles or trying to have kids he felt adding HCG to the TRT was more risk than benefit and wanted me to add .5 to my weekly TRT injections for a month prior to my next lab.

Despite the increased performance anxiety and addition of the TRT, I do feel something changed in how my body absorbs and responds to PDE5s. Like I said, for almost two decades, 25mg of Sildenafil with the occasional titration up to 50mg worked wonders for me. Instant facial flush, stuffy nose, spontaneous erections, a good hard on throughout sex. As i mentioned, I could lick just a droplet of crushed Sildenafil powder and get the facial flush. Often all of that within 30 minutes. I can take 200mg of Sildenafil now and have none of those side effects. I can still get a nice erection but maintaining it throughout intercourse has become difficult as has ejaculating. And there can be random spontaneous erections even 4 to 6 hours after dosing or hours after not succeeding with or finishing intercourse. I know the general consensus is the pills don't lose effect, your ED worsens over time, and I'm sure there's truth in the your ED worsens part. However, in my case, it has to be something with how my body is metabolizing the meds since the always customary side effects vanished even with higher doses (with the exception of heartburn at the end of the night) or my body up upregulating the enzyme in response to using the meds for so long. It's also not a matter of just switching up PDE5 inhibitors as they all require higher than recommended doses for the best result.

I share your view. It happens with many drugs. Let's say you take a strong antihistamine as sleep aid. If you've never taken it before chances are you'll sleep and feel like a zombie the day after. Keep taking it and likely the effect on your sleep will be less and the day after you will feel just a little bit tired. Then you may try to take small doses on almost daily basis, and you'll see that at best they will make your sleep onset easier, at worse nothing but the day after you won't have relevant side effects.

While I agree with the fact that ED worsen, I think you can"t have a reduction in the bad (facial flush, red eyes, etc.) without a reduction in the good (erection).

[Simbarn]

Wow. Thank you so much for such a well thought out response. I started the .25 Testosterone Cypionate w/ anastrozole twice weekly shortly after my divorce. While I'm sure the performance anxiety picked up being newly single and having new sexual encounters for the first time in 18 years, I've noticed a gradual worsening and more failures - even with combinations of high dose PDE5s - sometimes even with Trimix added in if I miss the mark injecting - the longer I've been on the TRT. I'm really not feeling any of the perceived benefits of TRT at this point. I'm still slow to recover from workouts, still have disrupted sleep, still have lulls in libido and ED issues, and still achy with focus issues. But my numbers and labs are really good. You just think I'd be feeling as good as the numbers.

Do you have a information source when it comes to your theory about TRT exacerbating the inhibitive sympathetic pathway? I' did a quick Google search and found this - https://www.swintegrativemedicine.com/b ... s-cause-ed - which speaks to the cortisol spike if testosterone is too high possibly attributing to ED. I mentioned the HCG to my doctor and he tried to ween me toward peptides instead. Didn't quite understand that. He told me that unless I was worried about the size of my testicles or trying to have kids he felt adding HCG to the TRT was more risk than benefit and wanted me to add .5 to my weekly TRT injections for a month prior to my next lab.

Despite the increased performance anxiety and addition of the TRT, I do feel something changed in how my body absorbs and responds to PDE5s. Like I said, for almost two decades, 25mg of Sildenafil with the occasional titration up to 50mg worked wonders for me. Instant facial flush, stuffy nose, spontaneous erections, a good hard on throughout sex. As i mentioned, I could lick just a droplet of crushed Sildenafil powder and get the facial flush. Often all of that within 30 minutes. I can take 200mg of Sildenafil now and have none of those side effects. I can still get a nice erection but maintaining it throughout intercourse has become difficult as has ejaculating. And there can be random spontaneous erections even 4 to 6 hours after dosing or hours after not succeeding with or finishing intercourse. I know the general consensus is the pills don't lose effect, your ED worsens over time, and I'm sure there's truth in the your ED worsens part. However, in my case, it has to be something with how my body is metabolizing the meds since the always customary side effects vanished even with higher doses (with the exception of heartburn at the end of the night) or my body up upregulating the enzyme in response to using the meds for so long. It's also not a matter of just switching up PDE5 inhibitors as they all require higher than recommended doses for the best result.

I had a gut feeling that TRT was affecting sympathetic function in the body, specifically the penis, so I did some research and it may affect the expression of A1 adrenergic receptors. Normal physiological amounts of testosterone shouldn’t affect this in a detrimental way, however excessive amounts may and I think even a slightly elevated prolonged increased level of T could do this in some males.. As exogenous T does not mimic the diurnal rhythm of T in the body, there is a possible consistent high level, even this could disrupt how receptors to Testosterone react, especially over a period of many months to years.
It took me some time but I found a few papers that may be relevant. I do not think there has been much research done on this topic. PM me if you would like me to email you those papers.
The possibility you mention that excessive testosterone may increase cortisol could be quite true, I would say it may actually increase adrenalin as well in certain situations and or how receptive we are to it.
For guys that may particularly susceptible to ED from slightly elevated levels of catecholamine’s systemically or even just in the penis (as norepinephrine can be released just in the erectile tissues) the above may cause issues.

Is there a reason why you are taking anastrozole with your TRT? Did you start using this when you began using the injectable T? Aromatase inhibitors can be unpredictable and can disrupt libido and sexual function terribly. I have avoided using them.
The anastrozole may be why you are feeling so awful, it could be driving your estrogen too low causing the focus and achy joint issues. Once estrogen gets too low with these drugs it can take some time for things to get back to normal after DC.

I don’t think your doctor understands that LH does more than just make your testicles bigger! The complete loss of this hormone and most probably the others I mentioned can cause many issues for guys, so much so that TRT can be just not worth it.
What peptides did he suggest using to replace the loss of upstream hormones? His suggestion of increasing the T to compensate for the above is IMO only going to make things worse. All this will do is further increase side effects and E2 conversion, it may give you a burst of energy for a short period until all the other issues set in.
I find it frustrating that there are many doctors that do not understand how detrimental it is to lose the production of gonadotropins and other hormones from TRT. Some form of replacement is needed for some men in order to have adequate sexual function.
I cannot stress enough, that more issues occur with regard to TRT from doctors prescribing too much Testosterone and then combatting the excessive E2 levels this causes by using an aromatase inhibitor, which then causes more problems.

There is a reasonably new form of T replacement called Natesto. From what I have been able to understand about this; it’s a very short acting T ester which is administered intra-nasal 3 times a day, as it is only short acting it may not significantly disrupt the HPTA. This has a very significant advantage over other forms of TRT, all of the natural hormones concerned with sexual function and their other functions in the body are for the most part preserved, plus fertility and ejaculate levels. The three daily doses of T are apparently enough to increase levels of T during the day, as the HPTA is functioning, T levels into the night are preserved. This could be an answer for some men who do not feel good with complete HPTA shutdown, mostly younger men with lowish T levels. It may not be suitable for guys with very low testosterone.
https://www.practiceupdate.com/content/ ... ity/100583
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480784/
https://www.auajournals.org/doi/abs/10. ... 0000001078
https://www.goldjournal.net/article/S0090-4295(20)31480-1/pdf

The main issues I see with this form of TRT is irritation to the nasal passage for some men and remembering to do it 3 times a day!