The Big Picture

General Discussion
#1

It seems to me that three distinct mechanisms are at work here:

  1. Those that shut down the HPTA…presumably this has to occur through some kind of “overstimulation” of the negative feedback mechanisms of the hypothalamus. Using finasteride causes increased T, decreased DHT. Because DHT is an estrogen antagonist, low DHT results in increased estroiol. With increases in both T and E, negative feedback on the hypothalamus produces an effect similar in mechanism to Anabolic Steroid Induced Hypogonadism, the result being hypogonadotropic hypogonadism. This effect could be amplified if the individual consumed CYP3A4-inhibiting factors while on finasteride. Symptoms would manifest themselves over time, and so explain cases that arise later and persist.

  2. Partial androgen insensitivity syndrome…meaning that, congenitally, some rare individuals have either a) androgen receptors that are less responsive to androgen, or b) lack of function in one of their two AR genes. In either case, we can imagine a scenario in which prior to finasteride use the individual was making just enough androgen to support penile tissues. Then, following finasteride administration, the individual experienced a decline in androgen activity such that AR was no longer activated to the extent necessary to maintain penile tissues, thus causing ED. The individual continued with finasteride nevertheless, assuming reversal of symptoms would be possible at any time, unknowingly causing permanent/long-term damage to penile tissues.

  3. Allopregnenolone deficiency. Symptoms (anxiety, depression), I would think, would only persist while on finasteride…The only possible long-term effect I can imagine would be neurodegeneration (i.e. excitotoxicity) in those areas of the brain that are vulnerable to the degenerative effects of glutamate. If this were in fact the case, progesterone cream could be considered curative (in addition to HCG, perhaps).

Theory #2 accounts for those individuals who experience immediate sexual dysfunction, as well as those who experience immediate ED followed by prolonged ED that doesn’t respond to TRT. Theory #1 accounts for what I would say is the majority of those experiencing long-term side effects: low gonadotropins in a setting of low T that manifests itself symptomatically as unresolvable low libido, low energy, anxiety (low T-induced), etc.

There are certainly shades of gray here, and possible confusion as symptoms of the above mechanisms would surely overlap, but this framework does seem to have universal explanatory power…as far as I can tell. But, naturally, I’m guaranteed to be missing something.

Any thoughts?

#2

I have a question, do you think to fit into your second scenario you would have had to have taken it for a while, i.e. at least a few months?

I’m just asking since I only took it for about 2 weeks or so.

If I had to pick one that I fit into it would have to be the 3rd one since

  1. I haven’t taken it for a long time at all
  2. My sex hormone levels aren’t bad, especially my free T, not only that but I haven’t lost any muscle, quite the contrary since I’ve gained about 10 pounds and none of it is fat, I also still have my mental vigor
  3. My progesterone and ACTH levels are weird. I am pretty confused though, because to try progesterone cream don’t you need a low level of progesterone? I have a high level of DHT, something here is definitley messed up…

I just wish a doctor could figure this out and I could have my freaking life back!

#3

Don’t forget that Finasteride is by design a 4-azasteroid, a Testosterone analogue.

I have put forth the theory before that because of what Finasteride is (Testosterone analogue), in essence it was as if we were taking exogeneous T/anabolic steroids for a prolonged period of time – WITHOUT cycling to prevent HTPA shutdown, as bodybuilders typically would.

Such a possibility, coupled with the upregulation of T due to lack of DHT from Fin, plus increased Estradiol due to aromatization of extra T, would be a triple whammy to the HTPA via extreme negative feedback.

So why didn’t everything go back to normal when we quit? Well for most here, there is a brief recovery period approximately 1-2 weeks after stopping the drug, however it is often shortlived (a week at most) before things start going downhill again.

Perhaps the rebounding DHT, combined with already elevated Estradiol, worked together to lower Testosterone production via negative feedback on the HTPA after quitting (rebounding high DHT + already high E2 tells HTPA to lower T output)… whereby the HTPA settles on a new, lowered T level from that point forward.

Most men that have PAIS are born that way, but perhaps the drug induced such genetic changes by mutation in the AR in normal men via the androgen-deprived environment created by Fin… there are studies out there that link AR genetic mutations to AIS. Also keep in mind that Finasteride DOWNREGULATES the Androgen Receptor… which means a decline in function.

The only way to know for sure what’s going on 5-alpha reductase enzymes and Androgen Receptors is by genetic testing to evaluate DNA. Regardless what you present is certaintly plausible, however without baseline testing before taking the drug it would be impossible to prove what the “minimum” level of androgen was required for us to function healthily. Also, some who have tried TRT have reported feeling no different – leading me to believe that perhaps its an issue with severely downregulated/less androgen receptors, a change in receptor function, or possibly a neurological issue (ie, neurosteroids/catecholamines… such as dopamine pathways/receptor function)

Agreed, while on the drug Allopregnanolone is of concern but since many experience resolution of their anxiety/depression/panic attacks after quitting, it leads one to believe that normal production of Allopregnanolone has resumed.

The only troubling aspect would be due to possibilities of neurodegenerative diseases, but this would be far more concerning for those using Dutasteride since it blocks both types of 5AR, with 5AR-I being found in abundance in the human brain.

Regardless since Finasteride does more than block just DHT… ie:

  • blocks 5AR-reduction of Progesterone -> Allopregnanolone (via 5a-DHP)
  • blockade of 5AR reduction of Deoxycorticosterone -> 5aTHDOC (via 5a-DHDOC)
  • blockade of 5AR reduction of Androstenedione/Testosterone -> Androstanediol (via 5a-DHT)
  • interference with the GABA-A receptors, due to depleted Allopregnanolone

… who knows what the longterm neurological consequences of this would be over a long period of time.

Thanks for putting that all forward, hopefully we might be able to get some answers from docs on this at some point. Perhaps if you see Dr John again he could elaborate with his own thoughts on these concepts…

#4

Well, finasteride isn’t a testestosterone analog per se. I think the only real similarity is that their both classifiable as ‘steroid’ class molecules.

Research has also shown that finasteride has no affinity for the androgen receptor.

blackwell-synergy.com/action … ookieSet=1

“Finasteride has no affinity for the androgen receptor and exhibits no known androgenic, anti-androgenic, estrogenic, anti-estrogenic, or progesterone-like activity (136).”

Now this is interesting…and it’s something that I’ve completely failed to consider (Probably because I’ve just always heard of T and E involved in negative feedback).

Here’s some info I dug up on this forum: t-nation.com/tmagnum/readTopic.do?id=1268022
“Now, let?s talk about DHT and 5-alpha-reductase, in terms of LH and testosterone. In some studies (predictably), Dihydrotestosterone has been shown to inhibit LH and FSH secretion and serum testosterone concentrations. In addition, and very importantly for this discussion, the actual conversion process of testosterone being metabolized into DHT via this 5a-R enzyme may act in some way to inhibit Leutenizing Hormone Release (and ergo would inhibit your HPTA and natural testosterone production). Yeah, the actual conversion process is inhibitory, as (apparently) is the actual end product (DHT) to some degree (it’s part of the hormonal cascade and negative feedback loop that controls testosterone production). DHT actually has been shown in cell cultures to be as inhibitory to the LH response on LHRH as Testosterone itself.”

And this I found here: cancernews.mediwire.com/main/Def … eID=330548

“The secretion of GnRH, LH, and FSH are under the influence of several “feedback” molecules. Testosterone and its more potent metabolite DHT exert a strong negative feedback on the LH-producing cells of the pituitary and the GnRH-producing cells of the hypothalamus. Indeed, even small amounts of exogenous androgen have been shown to cause significant suppression of the HPG axis.”

If this is true, then obviously it changes everything. With finasteride, you increase T, decrease DHT, increase E. The lower DHT, then, should actually subtract from the cumulative negative feedback effect. But there is still a question of magnitude, which is now key here: how does the decrease in DHT compare to the associated rise in E in terms of potency on action upon the negative feedback mechanisms?

It’s hard to say, but one thing is for sure: such ratio of T/DHT/E is certainly not something the HPTA is used to, evolutionarily speaking. Our bodies expect that T, DHT, and E will always increase together. With the addition of finasteride, this becomes skewed. We now have T increased, DHT decreased, E increased. What does the HPTA make of this?

Interesting. I assume you mean that finasteride downregulates AR through its effect on sex steroids? Indeed this is true: ncbi.nlm.nih.gov/sites/entre … stractPlus

“However, when conversion of T to DHT was blocked by the 5-alpha reductase inhibitor finasteride, the levels of AR mRNA were considerably down-regulated by T (10-500 nM)”

“Estradiol (50 nM) was even more potent than T in decreasing AR mRNA levels.”

“Our results indicate that it is possible to modulate in vitro AR mRNA levels in the penile smooth muscle cells, and that under normal conditions DHT and T act as moderate up-regulators. When DHT formation is inhibited, the aromatization pathway of T to estradiol will prevail and induce a pronounced down-regulation of AR mRNA levels.”

So this is very interesting. It is the fact that finasteride allows E to dominate, that is primarily responsible for the downregulation of AR. In effect, it’s a double whammy. The finasteride-user is left with less androgen receptors as well as less androgens to bind them.

As a sidebar, also note that they found something called ‘platelet derived growth factor’ effective in upregulating AR…“With the exception of PDGF none of the treatments affected significantly cell growth, as measured by DNA synthesis and content.” A possible therapy?

#5

Who here knew anything about hormones prior to Fin?

I didn’t even know how important hormones were…cuz they were always fine. It’s crazy how life puts you into a situation and you can soak up all the information so quickly.

The one thing though, all this information is being put together and reviewed in bits and pieces. Has anyone sat down and read a book on Endocrinology to fully understand the body and pathology? I fear that by all this cutting & pasting of different studies and information (found via google searches) is sort of working backwards.

Just a thought. If anyone has picked up a book pls suggest it to others. Also, Hypo can maybe put together a brief summary of how the pathology of hormones works.

I think your theories are promising. Just wondering if they can be backed up with fwd thinking and not backwards (meaning propecia caused this…rather if one takes propecia this may result).

Jack

#6

How does one go about testing for allopregnenolone deficiency?

#7

The mention of platelet-derived growth factor got me pretty interested, so I decided to do some research and see how one can get a hold of this stuff. Basically I believe there’s two effective ways to raise the level of PDGF in the blood.

  1. Colostrum

Colostrum, also known as first milk, is produced by humans and cattle in late pregnancy and also right after giving birth. It is rich in many, many vitamins, amino acids, and other things, I am slightly skeptical about it though, since it does contain albumin, but then again it also contains GnRH so I wonder if everything could even out. You can go to this URL of a forum post to read more about it and a list of whats inside of it… They sell colostrum as a supplement, though I’m not so sure of adequate or significant doses, as you might actually need a lot of it, and I think it would also be expensive at such high doses. Oh and I guess if you have a wife who is in late pregnancy you could suck on some titties. :laughing:

http://anabolicminds.com/forum/supplements/50508-bulk-colostrum-powder.html

  1. Human growth hormone (HGH)

The beneficial effects of hgh have been discussed on this forum, and it is also claimed that GHB increases secreted HGH levels while sleeping. HGH is taken by many for anti-aging purposes, and it is also claimed to raise testosterone levels.

I guess some people sell PDGF too…

http://www.biomedcomm.com/store/hgh_gf_pdgf.html

Thanks for posting this, this is a great thread!! I have no doubt that everyone on here can recover.