This is pretty ridiculous that it took me this long to figure this out…
Alright, so in order for finasteride to create an effect similar to ‘anabolic steroid induced hypogonadism’, we would obviously expect to see similar effects during the process of shutdown. This would mean significant decreases in LH and FSH, as the HPTA is being suppressed.
Judging from the literature this does not appear to be the case:
Although, interestingly, LH and FSH were not signicantly higher as the investigators had actually predicted, but were more or less the same throughout.
If you look at the graphs, you can see that GnRH stimulation does tend to produce slightly higher pulses in the finasteride group than control, suggesting just the opposite of what our theory would predict (at least at the level of the pituitary).
In any case, they conclude that finasteride does not, in fact, alter LH and FSH significantly. And finasteride certainly, for that matter, does not bottom out levels nearly to the extent that anabolic steroids would.
“Both basal and GnRH-stimulated secretions of LH and FSH during finasteride treatment were, in fact, similar to the values observed before drug administration. The lack of any change in LH pulse amplitude and LH pulse frequency seems to confirm that finasteride, directly or indirectly through the increase in T levels and/or the decrease in DHT levels, does not have any effect on gonadotropin secretion.”
“An increase of approximately 15% in luteinizing hormone (LH) and 9% in follicle-stimulating hormone (FSH) was observed in patients treated for 12 months; however, these levels remained well within the physiologic range. Gonadotropin-releasing hormone (GnRH) stimulated levels of LH and FSH were not altered, indicating that regulatory control of pituitary-testicular axis was not affected.”
The big question in my mind is this: if finasteride is, in fact, causing negative feedback, is it really at all androgen-mediated?
The evidence suggests not.
Studies on dutasteride may be very informative in this matter, as we can assume from the start that this drug is knocking out androgens in the brain (importantly the hypothalamus and pituitary) in addition to the rest of the body. It appears to be consistently shown that dutasteride has essentially a null effect on gonadotropin secretion. See the below, for example:
This null effect, however, is actually a bit odd considering that dutasteride (and probably by extension finasteride) are causing a significant reduction in androgenicity in the brain, and thus, if anything, reducing negative feedback. However, it makes sense if we consider the other important effect of this drug: it increases estrogen. This is mediated by two mechanisms: the lowering of DHT decreases antagonism to E, and the increase in T increases the aromatase-mediated conversion to E.
In this light, it now begins to appear that if there is any true negative feedback occurring whatsoever, it must be estrogen-mediated.
Though this is purely speculation, we might then suppose that later, after coming off the drug, it is only these estrogonic mechanisms that are suppressed, and thus the cause of perpetual low T.
This logic provides reason for hope: SERM therapy might, in theory, target exactly the mechanisms disrupted by finasteride’s mode of action.
“Isolated hypogonadotropic hypogonadism may result from an acquired defect of enhanced hypothalamic sensitivity to E-mediated negative feedback.”
…As I have argued above, “E-mediated negative feedback” would seem to be the one and only kind of feedback to be expect from finasteride usage.
“Whereas direct T replacement therapy can further suppress endogenous gonadotropin secretion, treating IHH men with gonadotropins can stimulate endogenous T secretion and enhance fertility potential. On theoretical grounds, reversal of gonadotropin deficiency with CC might be expected to have a similar biological effect.”
So fin-users: before you at all consider TRT, or hCG, or herbs, or anything for that matter that acts somewhere in the pathway from the hypothalamus-pituitary to the leydig cells in the feedback loop, you’ll definitely want to try the SERM first.
The negative feedback absolutely does occur with the use of finasteride.
We often see increased SHBG and or estradiol and this often results in lowered levels of LH and tstosterone, this is something evidenced time and time again in the pathology of the men on this site.
First of all, I for one have neither high estrogens nor high SHBG (low basal negative feedback), yet still have gonadotropic hypogonadism.
Secondly, I’m speaking here of the type of negative feedback that actually causes a physical change to the hypothalamus/pituitary, so that even after the negative feedback ceases, one still experiences low gonadotropin production (as in, perhaps, my own case)…
As I understand things, hypogonadism induced by negative feedback occurs when the hypothalamus/pituitary is stimulated excessively with androgen or estrogen over a period of time.
During such overstimulation, pronounced negative feedback is occurring, and so we would expect to see decreased levels of gonadotropins during the overstimulation event.
In studies on the general populace, such negative feedback does not seem to be apparent in most studies.
Interestingly, however, there doesn’t seem to be a reduction of negative feedback either (increase in gonadotropins), as we might expect as finasteride is actually lowering androgenicity.
This leads us to two possible conclusions.:
These studies are of the general popullation, and are just that. Those with finasteride-related negative feedback-induced hypogonadism are simply individuals who were predisposed to begin with. Or,
Since these studies appear to indicate that gonadotropins remain relatively constant during finasteride treatment, despite the fact that androgenic activity has been reduced, we might conclude that it is the elevated estrogen that acts to induce excessive negative feedback (thus maintaining negative feedback at near equilibrium), and that it is this entrogen-mediated effect that has long-term consequences.
I was not commenting upon your case, I was commenting upon the negative feedback that is often seen in the manner I was speaking of. Hence the point that I don’t really think that is debatable whether negative feedback occurs post finasteride use as we see it quite often.
What you are referring to has nothing to do with “negative feedback”. What you are describing is a lack of gonadotropins due to a problem at the hypothalamic/pituitary level.
That is not so, negative feedback to the HPTA is far more complex than this simple explanation and negative feedback is something that occurs very quickly with any increase or decrease in androgens or estrogens. It is also possible to induce a problem at the hypothalamic/pituitary level with one course of anabolic steroids, it has been seen before. Everyone is different, your endocrine system is unique to you as an individual. Some people have very weak systems that be damaged very easily other people are more fortunate.
What does the above statement even mean?
Most people will have a “pronounced negative feedback” and a total lack of gonadotropins if they are given two packets of testogel for a couple of days. Negative feedback is not some weird phenomena, it occurs very quickly and readily with small amounts of external testosterone supplementation.
You’re talking about a subject you do not understand. This is just some daft quote.
The fact of the matter is negative feedback is typical in the vast majority of cases when you are dealing with any medication that increases or decreases testosterone.
It is hard to know what it is you are trying to convey.
What is your point?
P.S
Just not sure what the point of all this is. I mean we know that the negative feedback does occur quite often and we also know that the hypothalamu/pituitary can be damaged by endocrine affecting meds which can result in a loss of gonadotropins, so where is the debate?
Haha…I may, in fact, have no idea what I am talking about…
And I apologize Hypo, I’m not trying to be a charlatan here…I’ll be the first to admit that my understanding of these matters is novice at best.
Essentially, once again though, here is my core argument. I do appreciate any feedback of course…just getting my facts straight would in my book count as progress.
So, there has been speculation that finasteride-induced hypogonadism may occur in much the same manner as do anabolic steroids via pronounced negative feedback.
The question then, is that if this is the case, then where does this heavy negative feedback come from? Do we even know it’s there?
This is how I understand this - negative-feedback induced hypogonadism - that is…
I am, in effect, distinguishing between two forms of hypogonadism
One caused by metabolic imbalance (high estrogen, for instance), and
One caused by hypothalamus/pituitary dysfunction
Can finasteride cause the latter of these? That is what I am addresding here.
Please correct any of these assumptions if they are wrong.
Anyways, the point of all the “mixed evidence” I presented was to show that, in the general male population that participated in these studies, there were a paucity of data to indicate that negative feedback was occurring.
There, again, is an assumption I am making. I have never confirmed this point, but assumed it based on intuition: that above-normal negative feedback is required to cause HPTA shutdown (e.g. as in anabolic steroids)
Anyways, as you see in the above studies, subjects are tested periodically while taking finasteride.
If mechanism (2) from above were a true possibility, we should expect to see some degree of negative feedback occurring during the actual administration of the drug, should we not? We should expect to see LH and FSH suppressed.
Since we do not see this, I conclude that negative feedback-induced HPTA shutdown, that is, negative feedback that leads to hypothalamic/pituitary dysfunction as in anabolic steroid abuse, is simply not likely or possible.
I elaborate further on this, but this is the core argument.
Hypo, I do apologize if I sound daft. You know well that I do not mean to. I am applying logic and inference to the data as critically as I can. Perhaps I would do well to not dabble in such matters?
I have presented my points as clearly as I could above.
Please do correct my misunderstanding if I have played upon a false assumption or otherwise.
Well first of all, you need to know the general mechanisms by which hypogonadism occurs in the use of anabolic steroid use, otherwise the reference is of no use at all.
You have injury to the hypothalamus/pituitary that can occur where you end up with a lack of gonadotropins. That has nothing to do with negative feedback, it has to do with damage to the body.
You also have negative feedback induced hypogonadism via AAS where the problem is a lack of gonadotropins due not to injury but to elevated SHBG or estrogens etc that result in an inappropriate testosterone and or DHT level.
Then again in some cases, usually prolonged use you have damage to the testicles themselves and hypergonadotropic hypogonadism.
So you have at least three differing ways in which you can end up with hypogonadism as a result of AAS.
Yes.
It can cause and does cause hypogonadism via negative feedback as seen so often where people who have taken finasteride end up with elevated SHBG and or estradiol and it can and does cause hypothalamic/pituitary dysfunction in others.
We see a metabolic issue in some people and a hypothalamic/pituitary issue in others.
The latter is not a negative feedback issue; negative feedback has nothing to do with that particular problem as far as is known and anyone can see.
It is rare to see testicular induced hypogonadism and elevated gonadotropins post finasteride use, that is not typically seen.
One swallow doesn’t make a summer, this is a single and I might add flawed study.
Why are they taking blood tests whilst stimulating the HPTA with GnRH?
They say that LH was not lowered, yet on page 486 you can clearly see that LH is much lower in the finasteride group than it is in the placebo group.
Why have they not measured SHBG given that SHBG is a crucial mediator of androgens and estrogens and plays a dramatic part in the negative feedback cycle?
They categorically state that finasteride does not increase estrogens.
This is categorically and empirically wrong.
Finasteride often causes an increase in estrogens and in particular SHBG.
Merck even list gynecomastia as a possible side effect of propecia.
Gynecomastia is primarily caused by increased estrogens.
Not at all. The HPTA can be shut down by very modest increases in testosterone in a very short space of time.
e.g
I was on one packet of testogel 50mg of testosterone of which about 10% is absorbed into the body and I had an LH level of 0.1 (described as undetectable) after just 3 days.
The extent of suppression of the HPTA differs person to person, but the point is; no it does not take an awful lot of testosterone to do this.
When you have seen as many studies as I have and no about the subject matter, you start to pick up on certain traits in those conductiong the studies and you can smell out those who have no idea as to what they are doing.
That study is a balls-up and I wouldn’t trust those conducting it to get anything right quite frankly.
I am telling you that finasteride absolutely does cause a negative feedback at the HPTA in many people.
You often see a lowered LH level post use in the setting of elevated SHBG and or estradiol and resulting low testosterone.
This isn’t remotely debated by people who correctly understand the effects of finasteride.
I do not see the need to correlate the finasteride induced problems with anabolic steroid abuse, I just don’t see the need at all. The issue is at hand has nothing to do with AAS abuse.
What we do have is hypothalamic/pituitary damage causing hypogondism in some and “negative feedback” or metabolic hypogonadism in others with elevated SHBG and or estradiol resulting in lowered LH and testosterone levels.
What you are arguing doesn’t actually make any sense at all.
You are saying that LH levels are not lowered by finasteride as a man who has lowered LH as a result of finasteride….bizarre.
You are not alone in having lowered LH as a result of finasteride, if you go through the hormone section of the site and look through the pathology you will see dozens of men with lowered LH and testosterone post finasteride use.
You will also see dozens of men with elevated SHBG and or estradiol and resultant low LH and testosterone levels.
You are drawing misplaced conclusions from one flawed study and in then comparing apples with oranges.
I don’t think you are daft, I just think you are misunderstanding the nature of these things and placing a lot of weight in one flawed study. The study is not helping matters because it is so patently flawed.
I could go through it with a fine tooth comb and detail tons of things wrong with it, or you could just take my word for it and go and look at the hormone section of our own website.
Wow, thanks for laying that all out there. It is all much much clearer now.
So I would just ask one final question:
What, precisely, might the mechanism be underlying instances where there is resultant hypothalamic/pituitary dysfunction? If it’s not negative feedback-induced, then what might it be? Do you have any theories yourself on this? Are we really only capable of saying that it is mediated by elevated E and SHBG, but that the mechanism by which these act is totally unknown?
Why the hypothalamu/pituitary is damaged in some people with resultant lowered LH and testosterone is unknown. It is known by people dealing with these matters like Dr Shippen and Dr Crisler and forward thinking endocrinologists that this happens, but it is not known why.
As for SHBG and estradiol and how they lower LH and testosterone that is understood.
The hypothalamus cannot differentiate between estradiol and testosterone. When estradiol increases the hypothalamus is fooled into thinkin that the body has too much testosterone and so it down-regulates GnRH which in turn down-regulates LH, whcih results in less testosterone.
SHBG on the other hand binds testosterone and estradiol, but it binds with greater affinity to testosterone. This means that SHBG greatly amplifies estrogens at the expense of androgens which it inactivates. The higher the level of SHBG the lower the level of free testosterone and the higher the level of free estradiol.
Estradiol has a 200 times greater potency at the hypothalmic level than testosterone, so despite there being much less of it, (even where it is high in men), it still has the capacity to fool the hypothalamus into down-regulating GnRH which causes the pituitary to down-regulate LH.
So in effect SHBG has a big impact of how much estradiol you have in comparison to testosterone that is active in the body.
The hypothalamus is stupid, it only sees the total steroid load and on that basis decides what to do.
Far to much SHBG or estradiol is incorrectly thought to be too much testostterone and that causes the hypothalamus to tell the pituitary that less LH is in order…when of course that isn’t the case.
Thanks as always for taking the time to straighten me out on this stuff. Very much appreciated.
Alright…this is exactly what I’m looking for. I was already aware, of course, of the metabolic mechanism, mediated by negative feedback, for HPTA suppression, but this is really what most interests me (as it likely applies to my own case).
So now, setting causation aside, do you have any idea at all what the nature of this “damage” might be? Based on my own limited knowledge of this subject matter I can suggest three possibilities:
Damage to hypothalamic/pituitary neuronal cell bodies (irreversible)
Diffuse axonal degeneration of hypothalamic/pituitary neurons.
metabolic alteration within the neurons themselves (e.g. changes in receptor gene expression)
Number (1) would seem unlikely, as we know that one can have an intact hypothalamus/pituitary, as determined by MRI, yet still have said dysfunction.
So it would seem like the dysfunction must be attributable to either (2) or (3).
Can you provide any further insight whatsoever as to the nature of the dysfunction? Or do you think, at least as we currently stand, this matter should be regarded as a total black box?
I think you are jumping a mile ahead of what is comprehendible or answerable by even the worlds most advanced study centers let alone what is comprehendible or answerable in terms that a layman would understand.
The idea of gaining any understanding on this level is not credible. Even if the correct questions or answers were there, which they are not you wouldn’t comprehend anything being spoken of any way. It would be the equivalent of astro physics being explained to someone with no background in astro physics…just pointless. I mean even what you have postulated, with all due respect you have no idea of what you are talking about, the terms and concepts etc. I do not say this to cause any offense at all, I say this just because I can see that you are swinging around concepts that you have no grip on whilst struggling with the very basic framework of these matters. There is no reason why you should understand all this at all, so it is not an insult, far from it, it is understandable that you do not understand it.
From your point of view you, mine too;
We need to keep in mind the limitations of being a lay person; you need to understand that as a lay person you can only go so far.
It is important to know the basics from the point of view of your own health, it is good to have a greater more in-depth understanding so that you have a solid grounding in helping others and know exactly how you are being treated in comparison to what is possible, or should be happening etc.
But you have to know where to draw the line as a lay person.
A shorter answer would have been;
YES- regard it as a black box.
The point is we know of at least two mechanisms that exist that result in hypogonadism due to finasteride use. That is enough to help us try and get the correct treatment. If the full and incredibly detailed complexities of these problems are ever found and understood, maybe someone will be able to detail them in terms fit for the lay person, until that point though we have to settle for where we are and what we have;
You know more than you did prior to the start of the thread, that is something.
But, we are not part of the medical community, never mind specialised biochemists researching this ultra complex area, we cannot join them, we are not going to do some research in the shed in the back garden and find an answer in a Petri dish (being silly and over the top, but you understand what I am saying).
I understand that light refracts in water, but I do not need to know physics behind it. I used to design computer software, but I do not know how to make microchips…if computers did not exist tomorrow or their was no electricity, I would not know how to generate electricity and build the cpu.
I know what I need to know and a lot more besides when it comes to understanding hypogonadism. I actually know more than most endocrinologists, but that is over the top as it is and I certainly realise that I do not need to know much beyond what I do in terms of depth of information. It would be a virtually pointless level of detail to me at the coal face to understand to any greater depth than I do.
I can potentially benefit from understanding any shifts in medical thought, or basic to medium level understanding in concepts or changes/advances in pharmacology etc…staying up-to-date on what is going on in the world of hypogonadism…but this is not a higher level of detail, it is more a breadth of knowledge on one level.
That is my position on this; if you feel differently then you can of course do whatever you want as is your prerogative. But you would be better at the very least getting the groundwork in place and fully understanding the foundations of endocrinology and reading the following before remotely considering anything beyond that;
The Testosterone Syndrome Dr Eugene Shippen
Androgen Deficiency In The Adult Male
The Testosterone Revolution
I’d just say that I guess I don’t imagine that this issue is really pulling a whole lost of brainpower from medical researchers in the first place. Also, I guess I don’t imagine that this sphere of inquiry is too remote or too esoteric for my mind to penetrate.
Sure I don’t understand the underlying equations or quantum theory to explain why water refracts light either, but I do know that there is an abundance of resources available that I could use, if I wished, to enlighten myself on the matter.
I agree with what you say, but I think for someone who is really ambitious and persistent there might be something to be said for a little armchair research.
Do we think that at least the raw concepts are out there, to understand the mechanism of finasteride-induced dysfunction? Are the prerequisite ideas available in accessible literature for elucidating the mechanism? If so then perhaps a layman might not in fact be entirely helpless to formulate it.
But you are right, I do want to be realistic here…really know my own limitations, that is. I drew false conclusions about the relationship between negative feedback and shutdown, I should take the hint that this is a steep hill to climb.
Personally, my best bet right now, as far as I can tell will probably be to drop this inquiry here, while I allow Dr. Crisler to explore the problem using his hit-and-miss approach. I remember when I went in for the consultation, he rattled off a list of things he’d do to try and pinpoint the issue, including ultimately testing neurotransmitters at some point. I ought probably to allow the doctor to exhaust his own knowledge of causes before I start clawing for answers myself.
And in the end if it’s TRT then so be it, I suppose. Not the most desirable outcome, but nonetheless a solution. TRT, I guess, with the expectation the somewhere down the line the cause and remedy will be determined.
You do not have the understanding of the basics period. So yes this is way beyond you, you’re fooling yourself to think otherwise. Even if you developed your understanding by reading all the books I suggested, you would still not be remotely qualified to evaluate the high level/detail of the specific research, you would not be able to evaluate it whatsoever.
Maybe if you took the knowledge that you had, then went on a got a grounding in further endocrinology and then went onto to pass the medical exams as and then go on to specialize in the concepts involved in the research side of this highly detailed complex area of medicine, then maybe you might be able to evaluate the information that was out there. Even if you ended up a professor of endocrinology that specialized in research of the hypothalamus and bioachemistry……even then you might still find that the answers are entirely lacking or inconclusive.
The idea that you can understand this from your armchair is laughable and deluded in my opinion. But hey if you want a place to start, start with the books and read all of them before even considering anything else.
The idea that you can read research on random studies on the hypothalamus of rats or humans even in given settings that you do not have even the slightest comprehension of and somehow wing it and understand a piece of information is just crazy and nonsensical.
So start with the books because as it stands currently you are in the shed with the Petri dish……
Categorically not.
You do not have any and I mean any remote ability to decipher papers on these matters. You would not be able to differentiate between a paper that was relevant to your questions and one that had no relevance whatsoever. Even if you had the right papers, you still would be able to comprehend what was being detailed, you would have no means whatsoever of critically appraising or evaluating what was being said.
And as it happens, we categorically do not have the answers anyway….so the research has not even percolated down to the likes of Dr Shippen, Dr Crisler, etc….
You seem to think you could understand this stuff from your armchair. I very much doubt that Dr Shippen or Dr Crisler would be remotely able to understand this reseach, never mind you or me. It would require interpretation for these specialized and experienced doctors, it would require liaison and interpretation of those working in such researchers for these Dr to understand the bottom line. But Dr Shippen, Crisler and other drs in this specific field have access to all the research papers they need and any department or specialist who is working on the papaers….they have access to such people so that interpretation can be obtained.
You have you PC, a cackhanded medical password for limited articles and not much else. You have no access to the people involved in the research, none……you have your shed and your Petri dish.
If you feel I am harsh, I am sorry but I am painting the true picture as I see it.
If you think you can reach for the stars go for it……but start with those books and read then all first and foremost and then try and become a medical doctor so you have access to the correct materials and maybe try and become and endocrinologist and then go on an specialize in the correct area of expertise……and then come back and tell me what you then know in approximately 15 years time.
You also have to accept the limitations of modern medicine and the fact that everything is not known.
You have to accept the limitations of each doctors knowledge, you have to accept the fact that no one doctor specializes in more than one area usually…
And you have to accept that there are a million and one things that can be tested rightly or wrongly and sometimes you have to simply accept limited answers and try and find an answer to the ill health.
I think it is probably VERY likely that you and no doctor you see will ever know what exact mechanism caused you to be where you are today and you may have to just accept a treatment hit and miss approach and hopefully rectify your health….that is after all the most important thing.
The number of people labeled as idiopathic (unknown origin) in many fields of medicine and in hypogonadotropic hypogonadism is huge.,…
