First, as @orthogs mentioned above, raising systemic DHT will almost certainly not lead to preferential saturaton of important tissues. Research has shown that tissue concentration of DHT in prostate is ten times higher than in serum. That’s because DHT is produced locally in the tissues and the direction of transfer is from tissues to serum.
Second, if 5ar2 is damaged in certain tissues, that leaves 2 other enzymes to produce DHT in other tissues, which may be enough for serum concentrations to appear normal. Further, there is not a good correlation between serum concentration and tissues concentration of DHT, as per the same paper, which is cited in the following post of mine.Tribulus stopped working. What else works? Just because someone has normal serum DHT does not mean they do not have DHT insufficiency in certain tissues.
Third, people with PFS have been found to have higher level of precursor hormones (progesterone, free tesosterone). This is my hormonal profile as well. Higher level of precursor hormones is an attempt of the body to increase the synthesis of 5ar hormones, despite the malfunctioning 5ar enzyme.
Now, when serum DHT is raised through supplementation, this will fool the body that 5a-reductase is functioning properly through negative feedback loops, which in turn will decrease precursor hormones. It is not clear what the total effect on tissues DHT will be but it is clear that tissue concentrations of 5a-DHP and allopregnanolone will fall, as progesterone is reduced. This may lead to worsening symptoms.
I have personally observed this feedback effect. I have very high progesterone, well above range. When I started using DHT, my progesterone fell by 33%. This is described in the following post from the same thread as above: Tribulus stopped working. What else works?
Fourth, local application of DHT to the genital area works well for me. (WARNING: This may be carcenogenic.) It really matters where you apply it, how much you apply, and what the formulation is. In one of the posts above I describe the pattern of application that produces the biggest effect. No doubt such topical application cannot reverse all symptoms of PFS as DHT is lacking not just from the genital area but also from key nerves in the body and in the brain.
Fifth, I am not sure how many of you have joint pain, but I used to have extreme and highly debilitating joint pain. Administering DHT systemically all but eliminates the joint pain, depending on the dosage I use. This is extremely strong evidence that DHT deficiency is causative for joint pain. I hypothesize that soft tissues holding the joint together are DHT dependent and they weaken from lack of DHT, which results in weakened joints. I have additional evidence to support this conjecture (obtained before I even began DHT treatment), as the nature of my joint pain indicates it originates from the soft tissues (spreads along the muscles), and no joint abnormality was found on a MRI.
Sixth, Melcangi’s latest study clearly demonstrated that patients with PFS suffered from methylated 5ar2 gene. This is in addition to previous research finding low levels of 5a-DHP and allopregnanolone in spine fluid, as well as upregulated AR. The latter can easily be explained by low androgen signal due to low tissue DHT.
People have tried to argue that Melcangi’s study proves 5ar2 malfunction is not causative for PFS because only 50% of the sample had that finding. This is an extremely important point that needs to be addressed thoroughly, because failing to understand this point has held our community back for decades and will continue to hold us back going forward, no matter how much research is done on the condition. I may try to address it in greater detail in another post, but here is a short version for now.
Everybody knows and understands that changing the body’s hormonal balance exogenously can lead to a prolonged disruption of hormonal balance upon discontinuing the exogenous intervention, which manifests as hypogonadism. This happens in body builders who take various steroids and then discontinue them, and it is known as HPTA axis shut-down. This also happens in prostate caner patients who take a combination of anti-androgens (including finasteride) and then discontinue them. The latter group takes multiple years to go back to baseline. I may insert the chart from that study later.
Then why can’t we fathom that taking finasteride and then quitting can also lead to prolonged hormonal disregulation that will result in hypogonadism? In fact this disregulation may be very stable as a new equilibrium is established, and may need targeted intervention to change, although is likely to normalize over time by itself. In fact we have evidence that a fraction of PFS sufferers normalize with time. These PFS suffers don’t need to have any changes in gene expression to suffer from hypogonadism.
This is what Melcangi’s study shows as well - a fraction of people with PFS symptomology do not have gene expression problems. In other words, it is very likely that there are two types of PFS. What I would call PFS Type 1 represents hypogonadism secondary to hormonal disregulation. This type is likely to recover over time, especially as their androgen receptors are normalized.
Patients with the second type of PFS, PFS type 2, most likely suffer from malfunctioning 5ar2. This group is unlikely to recover following the same mechanisms as the first group. Put bluntly, these are the people who do not get better over time. They are also likely to have additional symptoms secondary to 5ar insufficiency that the first group may not have. It is important to note that this group may also have hormonal disregulation early on similar to the first group, in addition to having malfunctioning 5ar2, which may partially or seemingly completely resolve over time (but not upon closer inspection of tissue levels of 5ar hormones).
The two types of PFS, type 1 and 2, because they are very different conditions, are likely begotten in different ways. The first type likely happens after finasteride is discontinued and may be related to the degree of AR overexpression. The second type most likely happens suddenly, as a switch being turned off - including from a single pill of finasteride. This mechanism does not require any degree of prior AR upregulation.
Attempts to use one causal mechanism to explain both types of PFS is a mistake. This is manifest when people discount the role of malfunctioning 5ar2 citing evidence from people who do not have this irregularity. Similarly, a theory postulating the existence of a single causative mechanism cannot explain contradictory and apparently mutually exclusive circumstances of getting PFS (i.e. from a single pill vs. after AR upregulation and subsequent AR overwhelm). I talk more about this here: Initial Ideas - Working from First Principles