Quick Update: Andractim DHT gel does not seem to work very well using my method of application, although it still works. The custom made DHT liposome cream I used before works much better. My positive observations above are based on the cream formulation. I will write more about that soon and what I think it means.
Update: Turns out what I wrote in this post may not be true. Gel may be working almost as well as the cream, but something else that’s very important might be going on, which I will try to write about shortly.
This is a very important update about my experimentation with topical DHT. It adds a completely novel finding with very important ramifications for the development of a theory of PFS.
Summary: Applying DHT to non-genital skin for a day, i.e. withholding DHT from genital skin for 48 hours, led to a “crash” apparent in genital tissues. Whereas previously DHT applied to genital area had a strong positive effect on sexual function, it had no effect on sexual function upon resumption of application after the crash. Presumably, lowering DHT concentrations in genital tissues led to (further) downregulation of 5ar expression in the tissues, which is how I believe PFS happens in the first place as well.
I feared this might happen as I have long postulated that PFS (type 2) happens in conditions of low or rapidly falling DHT levels. Therefore, I was hesitant to skip a day of application but I grew too overconfident after my previous success. @orthogs also warned about this risk in a post above.
To remind you, I was getting a very good effect on sexual function from topical DHT applied on penis and adjacent areas. I had been doing that for many months with excellent results - sexual function increased to 15-20% from my PFS baseline of 2%
Most recently, as I described earlier, I changed my regimen from application twice a day to application once a day with total daily dose remaining the same. This lead to a dramatically better effect, where sexual function increased to perhaps 50-60%.
I speculated earlier about the reason for this improved effect. I think it is due to the fact that with a once a day application I had more cream to apply to a wider area thus reaching more of the key tissues and also more importantly - reach a higher DHT concentration in tissues, which may be more important than maintaining more stable but lower concentrations with twice a day application.
I wanted to test whether the improved effect was due to the systemic effect of spiking DHT concentrations on the brain or on other circulating hormones. For a while I also wondered whether the improved effect might be due to a more extreme DHT withdrawal with a once daily application. This is where I left off previously.
To test this, I applied an equivalent amount of DHT gel (not cream) on non-genital skin (upper abdomen) to test the purely systemic vs. previous local tissue effect. I am very sensitive to the total systemic dose of DHT and I am confident the dose was the same, even though the formulation was different (I changed the formulation in order to conserve the cream which is in short supply). This was the first time in months I had skipped a regular DHT application to the genital area.
This method of application resulted in a much worse (practically non-existent) effect on sexual function. I concluded something I already knew from before - that systemic administration did not have much of an effect on sexual function and it was entirely local application that let to positive results.
After this test, I resumed DHT application to genital area. However, I continued to use the gel. I was rather shocked to discover that the gel had no effect on sexual function, while its systemic effect (on joints) was the same as the cream. I concluded that, while it is absorbed equally well systemically, the gel reaches lower penetration and concentration in tissues, unlike the cream. The cream is a liposome formulation and liposomes are known to deliver higher tissue concentration of active ingredients.
The following two paragraphs describes a side experiment but it is still informative. On the next day I mixed the DHT gel with a non-medical oil-based cream. The gel is alcohol-based and the alcohol evaporates very fast, which makes it hard to apply the formulation to a wide area, nothing to say about putting it on mucose skin. I used the same amount of gel as before (about 2 grams).
During the application, I immediately noticed the absence of the typical rush I feel when I apply DHT. My suspicion was confirmed the next day when my joints started hurting which is strong evidence that my systemic DHT dose was much lower. I also had no effect on sexual function. I concluded that mixing the alcohol based DHT gel with an oil based cram somehow chemically deactivates the DHT.
Then I resumed regular local application using the DHT cream, following the same protocol I had used before that was producing the improved results. To my surprise, I discovered that it had no effect! I used it for a couple of days in a row without any significant improvement. While before I was at 50-60 percent of sexual function now I was at zero.
I had crashed!
I never thought I would utter these words but it happened.
Next, I will describe why I think this happened and more importantly what I think this implies for the etiology of PFS. Stay tuned.
Sorry for asking this very amateurish question but how do you think is it possible that a topical cream used for the genital area can spike libido and arousal (thus in the brain)?
Thank you for your efforts trying to better understand this
It is a good and reasonable question and it has been asked before. I have attempted to give an answer but I can try again.
Libido and arousal are not only in the brain. There is a whole chain of organs and tissues participating in the process and they all play their part. This is not appreciated or understood very well I think.
My experiments have shown me, and that is a result which might be of interest to science in general, that partially restoring the function of sex organs and associated nerves through DHT improves sex response and its perception along the whole chain.
I cannot say if PFS has affected only said organs or also parts of the brain. I assume the latter. Certainly the pudendal nerve can’t be the only nerve affected. So obviously I have not been able to target tissues along the whole chain.
This is reflected in the fact that success was only partial at the peak of my improvement and it was certainly still lacking a big part of the psychological component of arousal and libido. But some of it was back.
I have not measured my DHT recently. The post below describes how my hormones changed soon after I began DHT supplementation 7 months ago.
Before supplementation, my DHT was 175 pg/ml (300-850). After beginning of supplementation and at the peak of DHT concentrations (one hour after application of a fast absorbing liquid formulation), DHT was 605 pg/ml.
I have since reduced the dose to about half of what I used at the beginning but I apply it only once a day so I assume DHT fluctuates between 300 and 550 within a 24 hour period.
When I am at the high end of this range I don’t feel well cognitively. I function much better with lower DHT and I am sure my natural serum level before PFS was always in the low normal range.
Thank you very much for your kind and elaborate answer. I was surprised because my understanding was/is that a stimulus spikes arousal in the brain which would then lead to an erection. This is also my explanation why many of us experience weak erections if there is no constant manual stimulation (and even then a full erection is not always achievable). As far as I can see usually the brain reacts to a stimulus and then activates a physiological process leading to continuous and repeated blood flow to the genital. So as Long as youre aroused blood will be pumped and eventually kept within the genital whereas Masturbation without arousal/excitement in the brain lacks this important process thus reducing or shutting down the erection immediately after stopping manual stimulation. I hope i didn’t get too graphic but that’s my understanding of this matter.
Of course hormonal deficiencies also seem to play a role concerning the sustainability of the erection.
My reasoning made sense at least to me because if you’re distracted or in a not pro sexual atmosphere (thus not being aroused) the erection would also be difficult to achieve and/or easily lost.
Okay this proves my theory kinda wrong haha. It’s pretty bizarre because when I have these very rare windows everything works accordingly whereas otherwise it’s like I described above.
To me it’s also still a mystery how people claiming they feel absolutely no stimulation can get erect with viagra as it is said even in the package that an erection would only occur with viagra if you’re sexually aroused.
Yeah I mean that’s the only thing that works for me is the ability to get those. Otherwise no libido, and everything is super numb. Surprised I can even get erections with how little feeling there is
This is an important paper which demonstrates key points I have made above:
Serum and tissue levels of DHT are independent
Tissue concentrations in prostate and in other DHT producing tissues are much higher than in serum
Direction of DHT diffusion is from tissues to serum
“Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels.”
“[S]tudies in which serum DHT concentrations were markedly elevated by exogenous administration of DHT had almost no effect on prostate DHT concentrations, prostate size, and lower urinary tract symptoms (see “Intraprostatic Control Of DHT in the Presence of Fluctuating Levels of Circulating Androgens” and associated references). The reason for this highlights fundamentally important control mechanisms in androgen target tissues that finely regulate pathways for androgen synthesis and degradation to maintain DHT homeostasis. These intracellular processes do not appear to be affected by circulating DHT concentrations.”
“Although DHT enters many tissues through diffusion from the systemic circulation, DHT in the circulation does not diffuse into the prostate because DHT concentrations in the prostate are markedly higher than the systemic circulation (intraprostatic DHT is on average 6- to 10-fold higher than circulating DHT)”
“Suppression of intracellular DHT levels with 5AR-Is results in reduced levels of DHT in the blood due to reduced leakage of DHT from peripheral target organs”
Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels
Another paper that makes the same point as above: “Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.”
Relationships between circulating and intraprostatic sex steroid hormone concentrations
Abstract
Background
Sex hormones have been implicated in prostate carcinogenesis, yet epidemiological studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically-verified benign prostate tissue from prostate cancer cases.
Methods
Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically-verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race and age were assessed as potential effect modifiers.
Results
Circulating sex steroid hormone concentrations had low-to-moderate correlations with—and explained small proportions of variations in—intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2=0.21), followed by serum testosterone and tissue dihydrotestosterone (r2=0.10), and then serum estrone and tissue estrone (r2=0.09). There was no effect modification by Gleason score, race or age.
Conclusions
Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.
Impact
The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk.
This is not the best place for this post because it is about joint pain but because it adds more evidence for my theory of PFS, the bulk of which is contained on this thread, I am posting it here for now.
I would like to amend the post about joint pain above with some additional evidence. Previously I said that I believe joint pain results from weakening of the joint from lack of DHT. The second part is true - low DHT causes it, as I have confirmed to myself a hundred times, but not due to weakening.
Weakening, I imagined before, happens when there is pressure on the joint through use. For example, walking would weaken the joint. However, I have new evidence that when I take a low dose of DHT, I get joint pain even without moving. I can literary lie in bed all day, as I have done, and I would get hip joint pain if my last DHT dose was too low. Such symptom progression is more likely caused by something like inflammation.
Pain appears very fast when serum DHT drops below a threshold. I take DHT once every 24 hours now and if I delay my dose by a couple of hours or if I have taken a slightly lower dose, I get joint pain. When it first starts, pain is burning in nature and is rather diffuse. Upon administering transdermal DHT, the pain goes away after an hour and a half or so, which is rather astonishing.
In addition, before I began DHT supplementation, I also had elevated Rheumatoid factor IgG – 29.8 U/ml (norm up to 20.0), as described here: Joint pain. I have not measured this recently to compare how it has changed.
Finally, an important paper below explains the mechanism through which DHT protects against joint inflammation. This paper was sent to me by @Lw77.
Dihydrotestosterone inhibits interleukin-1α or tumor necrosis factor α-induced proinflammatory cytokine production via androgen receptor-dependent inhibition of nuclear factor-κB activation in rheumatoid fibroblast-like synovial cell line.
Abstract
Rheumatoid arthritis (RA) is a disease with significant gender differences in its prevalence and clinical features. Interleukin (IL)-1 and tumor necrosis factor (TNF) α produced by synoviocytes are principle inflammatory and destructive mediators of RA. We found that a potent androgen, 5α-dihydrotestosterone (DHT) inhibits IL-1α-induced production and mRNA expression of IL-8, IL-6 and IL-1β from RA patient-derived fibroblast-like synovial cell line MH7A. Promoter analysis of the IL-8 gene revealed that nuclear factor (NF)-κB activation is critical for its transcriptional activation by IL-1α, and DHT inhibited the IL-1α-induced NF-κB activation in a manner dependent on the androgen receptor (AR). DHT also inhibited the effects of TNFα on the cells overexpressed with AR, indicating that sufficient expression level of functional AR was necessary for the inhibitory effect of DHT on TNFα. These results suggest that androgen contributes to the prevention against RA and its gender difference by inhibiting IL-1α or TNFα-induced proinflammatory cytokine production from synovial fibroblast-like cells by inhibiting NF-κB activation in a manner depending on AR.
Soon I hope I will be able to write a detailed post trying to explain why I think I suffered a serious crash after I discontinued tissue application of DHT for 48 hours (but not systemic application). This is yet another extremely important piece of evidence that I wish I didn’t have. I will explain later why this is so important.
For now I will briefly attempt to explain the potential mechanism behind this crash, and more importantly, I believe, behind PFS in general. Keep in mind that this is an extremely schematic model which no doubt omits many intermediate steps and processes.
The most important factor to keep in mind is that DHT appears to positively upregulate 5ar expression - i.e. more DHT leads to higher expression of 5ar and even higher production of DHT, and vice versa. This is confirmed by the literature and I will cite references later.
Such a regulatory mechanism may appear paradoxical but it is not because there is another component in the regulatory system - namely the androgen receptor. The AR exhibits negative feedback - it gets downregulated when androgens are high and vice versa.
The two regulatory mechanisms, 5ar and AR, work in tandem to regulate the system. There is indeed evidence that DHT upregulates 5ar through the AR. When there are two components in the feedback system, only one of them needs to be capable of negative feedback, and this is the AR.
Here is how it might work. A reduction in, say, testosterone leads to lower production of DHT, which downregulates 5ar, which reduces DHT even further. DHT is halted from plummeting uncontrollably by upregulation of the AR, which increases androgen signal and upregulates 5ar back up until an equilibrium is reached.
However, if DHT falls too much and too suddenly, which is what I believe happens in PFS and also during a crash, the AR does not have enough time to upregulate itself in time to stop the rapid downregulation of 5ar. Once 5ar is silenced significantly, DHT is at a critically low concentration and even the subsequent up-regulation of the AR cannot shake the system out of the new bad equilibrium.
The reason I think I suffered a crash is because during the months of local DHT application to the tissues, the AR must have been downregulated relative to its preexisting state. When I withdrew the DHT, first there was a rapid drop in DHT, which is dangerous as described above, but also the resultant androgen signal in the tissues dropped below what it was before I started DHT administration (assuming there was no upregulation of 5ar by the DHT in the meantime, although this condition can be relaxed). Thus, 5ar was donwregulated even further (relative to PFS baseline) and I was left at a worst state than I had been before I began DHT administration. Now my regular DHT dose does not work any more.
Caveat: I have no illusions that this model is too simplistic. It absolutely is. The important thing is that it makes roughly the right predictions, which I think it does.
I believe this is the first time such a theory of PFS has been proposed. I am not particularly attached to the pieces attempting to make sense how PFS happens. Those may very well be wrong or be a lot more complex.
However, I feel fairly confident about the model’s predictions of when PFS happens (or at least what I refer to as PFS type 2) - i.e. in conditions of rapidly falling DHT or any conditions where the AR (and any intermediate processes) cannot keep up opposing downward pressure on DHT. I have written about this at length earlier in the thread and elsewhere.
Sibelio, have you looked at the theory behind how Zulresso works on treating women with post-partum depression? I think the onset of post-partum depression is triggered by high hormone levels during pregnancy and a similar kind of failure for everything to equilibrate after birth when there is a large step change in hormone levels.
As to back your theory up, i have some psychological (?) obsessions about my erections. So when i start to get an erection, sometimes, i think about my condition and my erection ends in the mid way. I can feel the bloodflow stop. Well, thats kinda very obvious though… i just wanted to say.
The treatment I was already doing was working incredibly well. Had I not discontinued it abruptly for two days and crashed, against my better judgment, it would have continued to work, as it was working for months on end.
I am yet to write more about what the results of my experiments mean - there are a lot of very important ramifications, which it seems are not realized by most people - and I intend to but I can’t do it right now because I am busy with other stuff.
It seems to me that a permanent solution, if it is possible, needs to achieve an increase in tissue concentrations of androgens (mostly DHT but perhaps T as well) and avoid their sudden withdrawal. Ideally this would happen endogenously - for example through exercise. This is a plausible mechanism for long-term improvement, at least theoretically.
Alternatively, the tissue increase of androgens may be done exogenously - either through DHT or Testosterone - although that route has challenges as I have mentioned. I continue testing this method and I am trying to find out if I can reverse the crash. So far there is no success.
The most immediate and cheapest experiment that can be done to causally demonstrate that (or investigate if) the cell’s androgen signaling regulatory mechanism can be crashed by lowering DHT is in cell culture. That is in addition to the other experiments I have proposed in the posts above.
