Again, you really know your stuff and you understand what is likely to work and the normal curve effects of pretty much any treatment. But you mention local DHT. Does that mean that Estrogel on the scalp works marginally better than pills say;it seems under that logic. I don't know and I keep going back and forth in my beliefs. Estrogel probably works at least marginally to pump up things for a while.
Well, we know that HRT in the sense of exogenous E2 can yield positive results. The degree in which this happens seems to depend on multiple factors like androgen sensitivity, time of dormancy, fibrosis etc. This is why results are unpredictable and HRT is by no means a cure for everyone. In theory, hairloss is completely local. That means, as soon as the local environment is devoid of androgens, hair will not miniaturize under the influence of systemic androgens. We are not considering age-related decline in hair quality hair, or decline due to
any other factors (pure Androgenetic Alopecia). Thus, we are striving to obtain a local environment devoid of androgenic activity. Drugs are entirely possible to be effective
only locally, and so is E2. So, I would go even further with your statement and say E2 is significantly more effective topically
as long as it is kept locally (since it achieves a concentration that is magnitudes higher than the systemic concentration). The crux here is obviously to keep the drug locally (a
dermal delivery) as opposed to Estrogel, which delivers E2
transdermally. Hence, Estrogel is a terrible choice for d
ermal E2, as it was designed to deliver E2
transdermally. So actually you are right, Estrogel is marginally more effective if not indifferent to systemic E2.
There are some ways to achieve a
dermal delivery, although they are not abundant. The best way is through nanoparticles. Nanoparticle assembly is very difficult and should be attempted in a lab. Furthermore, the stability of nanoparticles is variable. Currently I am experimenting with E2 loaded on a Azone/Laurocapram-based vehicle. Azone is currently probably the best agent for
dermal delivery that is easily incorporated. There are many studies on Azone, but one specifically for E2 is listed below. Of course, as mentioned, one also needs an AA and 5ARI for this to have any chance of succeeding.
However, all of this is theoretically. We do not know if systemic androgens still influence follicles despite having an optimal local environment. Possible ways in which this may happen are non ligand-binding or non-genomic effects, which do not rely on receptor binding of the ligand but on the mere presence of it. Collectively, these effects are sometimes called
androgen receptor signaling (for androgens). Contrary to my username I am a theorist, but experimentation is necessary in order to gauge what works and what does not work, at least for me individually.
Source: Enhanced buccal and mucosal retention and reduced buccal permeability of estradiol in the presence of padimate O and Azone: a mechanistic study.