Do Primary Guys Necessarily Get Shut Down with TRT?

[PeakT]

My own reading on the various internet forms over the past few years is that most of the so called experts feel that the testosterone dose for primary guys needs to be increased until LH and FSH are fully suppressed.

Why?  What's the reasoning here?

[Kierkegaard]

Thanks for being patient. 

K: What you're saying about primary guys seems sensible; they have normal HP signaling, so you'd think if TRT is dosed low enough there would still be activity. However, I can't comment further without knowing more about how low estradiol triggers the hypothalamus.

Presumably low estradiol would result in *less* inhibition of the hypothalamus (and, as we see with the study above, pituitary as well).  Much like low cortisol means less inhibition of CRH/ACTH, adrenally speaking. 

Shouldn't something similar apply to secondary guys? Our signaling is messed up to some extent, but if we get HP suppression with TRT then some feedback is working. If we start with low-normal LH/FSH then why would it be suppressed by low-dose TRT that increases T, but still to below-normal levels?

Awesome question!  I'd say it could be possible to prevent shutting down LH and FSH in this situation (note for the passer-by: this is my thinking, not a known fact).  By the logic of negative feedback for any hormonal axis, in this case the more you increase testosterone, the more your reduce GnRH in the hypothalamus and therefore LH and FSH in the pituitary.  Which means that if your "starting point" LH and FSH are low (like, say, 2.2 and 3.4), you have that much less wiggle room to lower them by adding testosterone, i.e., you can only add that much less testosterone before shutting it down.  Basically with secondary guys (not just with hypogonadism but also secondary hypothyroidism and secondary adrenal insufficiency), you have a much lower ceiling to increase testosterone before shutting down LH and FSH.  The lower your LH and FSH, the lower the ceiling.  If you have LH and FSH 2.2 and 3.4, respectively, then by negative feedback logic, you might only be able to have, say, however much cypionate results in a peak of 400 ng/dl.  If your LH and FSH are borderline, like around 5.6 and 5.3, respectively, you might be able to do enough cypionate to result in 600 ng/dl.  Does that make sense? I'd be interested in your response to this.

Pretty exciting stuff.

Here's a related question: Why don't aromatase inhibitors reverse the hypothalamic-pituitary suppression of TRT? Or do they to some extent? My understanding is that SERMs work in this application by blocking the estrogen (E2?) receptors in the hypothalamus. Shouldn't AIs accomplish something similar when they drive down overall E2 levels, or is there some added complexity here?

SERMS are a mixed picture to my understanding, because half of clomid, for example, is 40% estrogen antagonist, whereas the remaining 60% is estrogen agonist.  So they do block E2, but they also apparently increase it.  AIs, though, should (given the study above especially) lower the negative feedback inhibition of GnRH and LH/FSH.  So it should be theoretically possible that a guy's LH and FSH are low in a clear secondary way solely because of overaromatization -- it's his massive E2 that is shutting down LH and FSH.  Correct his E2, such as through the rarely used anastrozole monotherapy, and his E2 should lower, perhaps while also allowing testosterone to rise because of the same lack of E2 that previously was sucking up T.

Interestingly, there are multiple reasons for LH and FSH being inhibited.  One of them is excessive glucocorticoids; increase cortisol way too much and you lower LH and FSH, meaning a guy's cause of secondary hypogonadism could totally be excessive chronic stress, or (in rare cases) a Cushingoid benign tumor which causes huge cortisol levels throughout the day.  Or you also have CRH (the hypothalamic stress hormone that signals the release of ACTH in the brain while simultaneously increasing norepinephrine in a positive feedback loop), which also inhibits LH and FSH.  Where do you see high levels of CRH?  Chronic stressor where the person is (adaptively) pumping out lots of cortisol.  But, aha, you also see it in primary adrenal insufficiency and congenital adrenal hyperplasia states, where ACTH (and therefore CRH) are excessively high to offset relatively low cortisol.  This should mean, so bloody fascinatingly, that a primary AI or CAH guy could reduce his suppression of LH and FSH by getting on a physiologic dose of hydrocortisone, which raises his cortisol to a normal level and so vastly lowers CRH, ACTH, and NE, all of which probably are collectively responsible for a huge punch in inhibiting LH and FSH.  Whoa!  (I might be one of these guys, btw.)

[electrify]

Regarding chronic stress---

If chronic stress lowered LH/FSH by way of cortisol, then how come there are young people with all kinds of issues like depersonalization, anxiety disorders, depression have LH/FSH/T normal?

Like I wonder what determines whose Testosterone would get effected by chronic stress. Cause myself I am wondering if I could get a T bump by taking something like a dopamine agonist to give me motivation and lower my anxiety. And then after T recovers, I would be officially recovered and then that would be tapered off but idk if it can work like that...

[Kierkegaard]

My own reading on the various internet forms over the past few years is that most of the so called experts feel that the testosterone dose for primary guys needs to be increased until LH and FSH are fully suppressed.

Why?  What's the reasoning here?

My GUESS is that thoughtless docs are reading the literature about how suppressed LH and FSH is part of the process for secondary guys (for whom it's probably supposed to happen), and they irrationally generalize to primary guys as well.  Therefore even if a primary guy's testosterone is great while also having LH and FSH be just fine, the doc thinks, "hmm, something isn't right here, because the literature I've read [which is basically based on secondary guys] speaks of guys suppressing LH and FSH, so something isn't right here," and jacks up the dose. 

[Kierkegaard]

Regarding chronic stress---

If chronic stress lowered LH/FSH by way of cortisol, then how come there are young people with all kinds of issues like depersonalization, anxiety disorders, depression have LH/FSH/T normal?

Like I wonder what determines whose Testosterone would get effected by chronic stress...

Everyone's different.  And remember there are multiple channels by which LH and FSH are reduced.  Stress is just one of them, and maybe guys with depersonalization, to use one of your examples, have good resting levels of NE, CRH, ACTH, and cortisol, but get suddenly hit with a stressor that increases these hormones.  In the moment they'd get a kick to LH/FSH and GnRH, but because the kick isn't constant they don't chronically lower levels. 

Or maybe some guys get more of a kick -- sensitive receptors with the HPT axis? -- to their LH and FSH for their increase in NE, CRH, ACTH, and/or cortisol, whereas another dude gets much less of a kick to LH and FSH with the same increase in NE, CRH, ACTH, and/or cortisol. 

There are plenty of other reasons. 

[Cataceous]

My own reading on the various internet forms over the past few years is that most of the so called experts feel that the testosterone dose for primary guys needs to be increased until LH and FSH are fully suppressed.

Why?  What's the reasoning here?

Presumably the idea is that the lowest dose at which LH and FSH are suppressed could be close to the individual's "normal" set point if he had functional T production.

[Cataceous]

Shouldn't something similar apply to secondary guys? Our signaling is messed up to some extent, but if we get HP suppression with TRT then some feedback is working. If we start with low-normal LH/FSH then why would it be suppressed by low-dose TRT that increases T, but still to below-normal levels?

Awesome question!  I'd say it could be possible to prevent shutting down LH and FSH in this situation (note for the passer-by: this is my thinking, not a known fact).  By the logic of negative feedback for any hormonal axis, in this case the more you increase testosterone, the more your reduce GnRH in the hypothalamus and therefore LH and FSH in the pituitary.  Which means that if your "starting point" LH and FSH are low (like, say, 2.2 and 3.4), you have that much less wiggle room to lower them by adding testosterone, i.e., you can only add that much less testosterone before shutting it down.  Basically with secondary guys (not just with hypogonadism but also secondary hypothyroidism and secondary adrenal insufficiency), you have a much lower ceiling to increase testosterone before shutting down LH and FSH.  The lower your LH and FSH, the lower the ceiling.  If you have LH and FSH 2.2 and 3.4, respectively, then by negative feedback logic, you might only be able to have, say, however much cypionate results in a peak of 400 ng/dl.  If your LH and FSH are borderline, like around 5.6 and 5.3, respectively, you might be able to do enough cypionate to result in 600 ng/dl.  Does that make sense? I'd be interested in your response to this.

This all makes good sense to me. It makes me wonder how many variants there are of secondary/tertiary hypogonadism. Is the HP response clipped off or is there normal proportionality, but with attenuated activity?

[Kierkegaard]

Shouldn't something similar apply to secondary guys? Our signaling is messed up to some extent, but if we get HP suppression with TRT then some feedback is working. If we start with low-normal LH/FSH then why would it be suppressed by low-dose TRT that increases T, but still to below-normal levels?

Awesome question!  I'd say it could be possible to prevent shutting down LH and FSH in this situation (note for the passer-by: this is my thinking, not a known fact).  By the logic of negative feedback for any hormonal axis, in this case the more you increase testosterone, the more your reduce GnRH in the hypothalamus and therefore LH and FSH in the pituitary.  Which means that if your "starting point" LH and FSH are low (like, say, 2.2 and 3.4), you have that much less wiggle room to lower them by adding testosterone, i.e., you can only add that much less testosterone before shutting it down.  Basically with secondary guys (not just with hypogonadism but also secondary hypothyroidism and secondary adrenal insufficiency), you have a much lower ceiling to increase testosterone before shutting down LH and FSH.  The lower your LH and FSH, the lower the ceiling.  If you have LH and FSH 2.2 and 3.4, respectively, then by negative feedback logic, you might only be able to have, say, however much cypionate results in a peak of 400 ng/dl.  If your LH and FSH are borderline, like around 5.6 and 5.3, respectively, you might be able to do enough cypionate to result in 600 ng/dl.  Does that make sense? I'd be interested in your response to this.

This all makes good sense to me. It makes me wonder how many variants there are of secondary/tertiary hypogonadism. Is the HP response clipped off or is there normal proportionality, but with attenuated activity?

With secondary hypogonadism, the body makes GnRH fine but for some reason LH and FSH are low; you see the same thing with secondary adrenal insufficiency, where CRH is fine but ACTH is low.  With hypogonadism, secondary forms actually *should* cause GnRH to skyrocket, because the hypothalamus is picking up low testosterone levels in the blood and releasing GnRH to "shout awake" the underperforming LH/FSH.   

That's just secondary hypogonadism.  I've never met a single guy who has had GnRH pulled, and really there's no reason (if you have secondary or tertiary, treatment is the same: testosterone injections).  Tertiary is where GnRH itself is underperforming, whicih causes low LH/FSH, which causes low testosterone.  Same thing with adrenal insufficiency, where tertiary AI means CRH is low, leading to low ACTH and therefore low cortisol. 

[Kierkegaard]

The reason I think a thread like this is important -- the main reason I started rambling on it -- is my theorizing that secondary guys of any form (thyroid, adrenal, testosterone, etc.) probably are much, much more likely to suffer from shutting down their hypothalamic (TRH, CRH, GnRH, respectively) and pituitary (TSH, ACTH, LH/FSH) hormones given the "ceiling" talk I mentioned above (secondary forms of hormonal deficiencies meaning much lower ceilings and therefore theoretically much lower doses to correct it without shutting down these hypothalamic or pituitary hormones).

This is very, very important for guys who are considering, say, hydrocortisone when they seem to be suffering from secondary adrenal insufficiency.  This means they have a much shorter trial time to try out HC before they shut down CRH/ACTH and therefore their own endogenous production of cortisol, so this means they're stuck on life for this hormone even if they just wanted to try it out for a while.  And you don't fuck with cortisol, the only hormone you can't live without.  It'd be hell enough having secondary (i.e., not the typical type, which is primary) hypothyroidism and shutting down TRH and TSH; that would mean stopping exogenous thyroid hormone would mean your body is "starting from zero" like with secondary hypogonadal guys when they want to stop testosterone after shutting down LH and FSH.  Not good.  But doing this with secondary adrenal insufficiency and inappropriately (i.e., suddenly, without tapering very, very slowly, which might not work at all) stopping HC could put you in the emergency room with an Addisonian crisis because your body, after stopping HC like this, would effectively have almost no cortisol of its own. 

So what I'm trying to get to is the idea that primary guys, whether with hypothyroidism, adrenal insufficiency/congenital adrenal hyperplasia, or hypogonadism all have lots and lots of wiggle room to utilize exogenous hormones without even coming close to shutting down their respective hypothalamic and pituitary hormones.  This is important stuff to know.

Also consider the "good deal" primary guys have with hypogonadism.  Unlike secondary guys, who totally suppress LH and FSH, primary guys can have good or even slightly high LH and FSH after getting testosterone levels to good physiological ranges and feel a lot better.  Their good levels of LH and FSH means they have very healthy levels of pregnenolone given the influence of LH and FSH (and ACTH) on converting cholesterol to pregnenolone via the p450scc enzyme; healthy levels of pregnenolone means all their adrenal hormones are good, including progesterone, allopregnenolone, DHEA, and perhaps most importantly cortisol.  You really don't want to shut down LH and FSH if you can avoid it because of the effect on pregnenolone-line hormones. 

The study below puts into numbers what plenty of guys have noticed if they're secondary hypogonadal guys and get on TRT and so have lower levels of preg, prog, and especially DHEA because of shut down LH and FSH: it notes a testosterone-moderated 30% reduction in ACTH-stimulated pregnenolone for adrenal cells in rats, and (super interestingly) an estrogen-moderated 50-something% increase in pregnenolone (another reason why estrogen is important).  Here's the abstract (which I'll be created a thread over with other fascinating testosterone influences on adrenal points later):

Effects of sex hormones on the steroidogenic activity of dispersed adrenocortical cells of the rat adrenal cortex.

• The effect of 17 beta-estradiol and testosterone on glucocorticoid secretion were studied in vitro by using dispersed inner adrenocortical cells obtained from gonadectomized female and male rats. Independently of the sex of animals, estradiol enhanced basal, but not ACTH-stimulated corticosterone (B) secretion; conversely, testosterone inhibited ACTH-stimulated, but not basal B output. HPLC analysis of steroid secreted demonstrated that estradiol induced comparable rises (53-62%) in basal pregnenolone (PREG) and total post-PREG secretion (progesterone, 11-deoxycorticosterone and B). Testosterone inhibited by about 30% ACTH-stimulated PREG production and by about 54% total post-PREG secretion (B was decreased to 56% of the control value, and other steroid hormones were below the limit of sensitivity of our assay system). These findings indicate that sex hormones directly affect rat adrenocortical secretion, mainly by acting on the rate-limiting step of steroidogenesis (i.e. the conversion of cholesterol to PREG); moreover, they suggest that testosterone is also able depress the activity of the enzymes operating distally to cholesterol side-chain cleavage.

Yes, these are rats, but the fitting decrease in pregnenolone via testosterone fits the experiences of endless guys, and is why Dr. Crisler wisely speaks of "backfilling" hormones when on exogenous testosterone by using pregnenolone, DHEA, and hCG. 

There's also a "post-pregnenolone" decrease mentioned here, which refers to key adrenal enzymes that get inhibited with testosterone, namely (in this study) 3b hydroxysteroid dehydrogenase and (in other studies I'll be showing later) 21 hydroxylase and 11b hydroxylase, which you can see in this chart:



Guess what?  These three enzymes are exactly the enzymes you see in people with congenital adrenal hyperplasia.  So if you're the unlucky type who really gets hit by these enzymes, this means you'll have cortisol (among other things) lower at a relative level, meaning (according to Dr. Jefferies) the body will compensate by jacking up ACTH to get the body to its preferred set point for cortisol relative to stress at the moment and diurnal rhythm.  This means cortisol will easily appear normal (or even high relative to stress) while CRH and ACTH are much higher to get a normal increase in cortisol, and the higher the CRH (and ACTH) the more you're going to activate your SNS, given CRH's positive feedback relationship with brain norepinephrine.

This shit is unimaginably fascinating and important for driving home my long-suspected belief that exogenous testosterone, especially if it's not supplemented with pregnenolone (and even here you're having slight downticks in the adrenal enzymes mentioned below, which can cause problems in susceptible guys who can supplement with pregnenonlone all day long without circumventing these adrenal enzyme reductions), lowers adrenal hormones, and therefore cortisol (at least relative to ACTH).  Basically, exogenous testosterone turns down pregnenolone as well as CAH-type enzymes, which might explain some of the symptoms guys get on testosterone-only TRT, such as bloating (increased 11-desoxycortisone levels and other salt-retaining hormones given adrenal enzyme downregulation), water retention, and high blood pressure. 

Note that the vast majority of guys on exogenous testosterone aren't going to feel anything with these enzymes being downregulated, solely because of how much better the vast majority of guys feel on testosterone-only TRT.  But still, it's important to know that pretty much everyone is getting in varying degrees a slight downregulation of key adrenal enzymes (including pregnenolone production itself) when on exogenous T.  This might be an argument for everyone adding hCG to TRT or just trying clomid instead. 

[Kierkegaard]

And man oh man, let's just repeat my last statement here:

"The study below puts into numbers what plenty of guys have noticed if they're secondary hypogonadal guys and get on TRT and so have lower levels of preg, prog, and especially DHEA because of shut down LH and FSH: it notes a testosterone-moderated 30% reduction in ACTH-stimulated pregnenolone for adrenal cells in rats, and (super interestingly) an estrogen-moderated 50-something% increase in pregnenolone (another reason why estrogen is important)."

How could this be important for testosterone-taking guys with hypogonadism?  It could make a great argument for oldschool intramuscular injections over subcutaneous ones, given that IM guys should have a lower testosterone:estradiol ratio than subq guys.  Lower testosterone and relatively higher estradiol so long as both are at a good level would mean that the higher estradiol could, according to the study mentioned above, offset any reductions in pregnenolone from testosterone, which (again) will be higher in guys who do IM shots compared to those who do subq shots.

Perhaps one of the reasons why guys feel so much more worse with low E2 levels compared to high ones is that low E2 means your body is more at the mercy of testosterone to shut down pregnenolone production.  If estradiol were higher, it might counterbaance the loss in pregnenolone from T by increasing it.  As I've argued elsewhere, estradiol increases NE, ACTH, and cortisol significantly compared to controls, so you can add the understimulation of low estradiol (less NE, ACTH, and cortisol, at least when stimulated by stress) to this picture and can see why estradiol is so blood important for males.

This is all theory, folks, so don't take it too heavily, but I think it's a real possibility.

[Kierkegaard]

Peak, I'd be really interested in your thoughts on the last few threads, especially the adrenal enzyme inhibition stuff.