TRT

[burlyman30]

This thread is exclusively for the discussion of Testosterone Replacement Therapy.

[Jelisej]

I'll post some previous posts from PP:
TRT is complicated, and only for minority adding only or boosting only testosterone will work. In this case you start with HCG first, and if test. levels are insufficient you add testosterone as required.
Then you may need to add some thyroid hormones, that is so called " 1st generation male treatment"
For harder cases its "2ND generation treatment plan"
Treat multiple hormone imbalances with exogenous T and HCG, plus one or more of the following:
-pregnenolone to boost pregnenolone,
-thyroid hormones to boost thyroid hormones,
-either HC or prednisone or prednisolone or medrol to boost cortisol,
-florinef to boost aldosterone,
-DHEA to boost DHEA,
-DHT to boost DHT,
-Aromatase inhibitors to lower excess E2,
-avodart to suppress excess DHT,
-supplements to suppress excess SHBG (nettle root extract etc...)
-dostinex to suppress excess prolactin.

Then you have 3 generation treatment plan:
"Treat multiple hormone imbalances by restoring resting metabolic rate to youthful via preg/prog & T4/T3 supps - GH and T should recover so only add GH if GH is still too low, and only add T and HCG if T metabolism is still too low, after resting metabolic rate has been boosted to youthful."

4th Generation Male Treatment Plan:
Treat multiple hormone imbalances by first restoring leptin sensitivity via a low carb high protein diet, and then boost leptin levels

- - - Updated - - -

SERM as a TRT is no option, I'm afraid. Thet can only be use as part of "restart protocols", that's all.
SERMS work by blocking estrogens at some receptors but act as estrogens at others, and using them long term has side effects, plus in reality we still donkt know to much about them.
This is what some endos said:"I have fear for impairment of the brain's ability to protect itself from ischemic, traumatic and toxic insult while under the influence of this class of drugs, as the brain cells must be able to freely express alpha and beta estrogen receptors to do so."

Any SERM (Clomid, tamoxifen) definitely causes two main problems after long term use:

1) You can't use any commercially available labs to quantify how your E2 (estadiol) is working in your body. This is because:

...a) SERMS (ie: clomid and tamoxifen) block E2 receptors, so very few of the E2 molecules present in your body will ever be lucky enough to trigger an unblocked receptor. So most of the E2 molecules will simply be "floating junk".
b) Measurements of total E2 only measure E2 molecules (which are mostly "floating junk") but what is actually needed is to measure the number of moecules which get lucky enough to trigger an unblocked receptor.
c) There are no labs which can measure the "number of trigger events of unblocked E2 receptors". If we could measure this we would have a direct measurement of E2 metabolism. No such test exists.
2) Long term use of SERMs (ie: clomid and tamoxifen) cause eye issues - especially floaters

[Jelisej]

Aromatase inhibitors are usually also not good as TRT- majority of people do get "numbers" but they dont get "feel"

Hormones should be fixed in this order:
Adrenal
Thyroid
Testosterone
Growth Hormone

Both thyroid and estradiol have a big impact on libido, so even if testosterone and DHT are in good range- libido still may not be there if those two are off.

Some research showing results and charts of different treatment of hypogonadal patients:
The Androgen-Deficient Aging Male: Current Treatment Options

[Jelisej]

Very good post about TRT from Dr Romeo Marianco:

If a male is hypogonadal for an extended period of time, then the first exposure to testosterone replacement can be exhilarating. Then it eventually goes away.

Here is a simplification of what may be happening:

Testosterone increases dopamine signaling in the brain. Dopamine signaling promotes sex drive, attention, interest in activities, elevates mood, and is calming in effect since it also reduces norepinephrine signaling. Without testosterone, there may be an increase in dopamine receptor concentration due to the loss of dopamine signaling.

Testosterone, itself, has a calming effect on the brain. It helps reduce norepinephrine signaling. Losing testosterone loses another of the control signals on norepinephrine production.

The loss of testosterone production is also accompanied by a loss of testicular thyroid releasing hormone production. This results in a reduction in thyroid hormone production. This results in a reduction in metabolism and energy. The brain compensates by increasing norepinephrine production to increase energy. This increase in norepinephrine signaling can promote insomnia, irritability, anxiety. It also does not usually improve energy well.

Over time, with aging, thyroid hormone production is reduced. This compounds the problem of thyroid loss accompanying testosterone production loss, including a further increase in norepinephrine signaling to compensate for the loss.

Testosterone, overall, is an anti-inflammatory signal and helps govern adrenal function, preventing excessive production of cortisol. Without testosterone, under increased norepinephrine signaling levels, high cortisol production may occur - which may or may not cause problems.

The elevated norepinephrine signaling may then be accompanied by pro-inflammatory cytokine signaling as the brain becomes chronically elevated by stress signaling/norepinephrine. Over time, this may then cause hypothalamic-pituitary-adrenal dysregulation with low cortisol production.

Estradiol, functioning as an MAO, increases serotonin greater than norepinephrine. It promotes competitiveness, drive, sex drive, aggressiveness. Without testosterone, however, and the dopamine increase it promotes, Estradiol would tend to flatten sex drive and promote irritability and aggression, anger, instead. Unless testosterone production is very low, Estradiol can be maintained since so little in relationship to testosterone, is needed in men. The relative change in signaling strengths of each poses problems of excessive estrogen. This includes increased thyroid binding globulin and reduction of free thyroid hormone signals. Excess estrogen, by increasing serotonin excessively, may reduce sex drive.

Norepinephrine is important for sexual function. It promotes the high and excitement that accompanies sex drive / libido. But in excess, it does not. It causes tension, stress, distress, anxiety, irritability, which lowers sex drive. To increase norepinephrine, the brain may reduce serotonin, GABA, then dopamine production - causing problems with deficiencies in serotonin, GABA and dopamine.

Excessive norepinephrine production also causes insulin resistance. The increase in insulin production that results is pro-inflammatory. It also further reduces testosterone production. Insulin also promotes fat storage. The resulting increase in fat results in an increase in Leptin and other pro-inflammatory signals from fat cells.

And so on and so on. These are some of the changes that permeate the system from the loss of testicular testosterone production. Some are added to by changes in the metabolism of the other cells which produce other signals such as thyroid hormone, through the process of aging or with nutritional problems or with genetic predisposition to other signaling or metabolic problems or through structural changes such as the loss of cells in the hippocampus and other brain structures.

-----

So what happens when testosterone is replaced?

There is a reversal of some of the initial signaling problems.

Because there is a larger number of dopamine receptors from the dopamine signaling deficit caused by the loss of testosterone, there is dopamine supersensitivity to the surge of dopamine signaling that accompanies the increase in testosterone with replacement. This can cause a high - with heightened sex drive, alertness. and an elevated mood.

Testosterone would also free up thyroid hormone by reducing thyroid binding globulin, reversing estrogen's effects, improving function from this angle. This would improve energy

Testosterone would then reduce excessive norepinephrine signaling, which as it comes more in normal physiologic strength, helps dopamine in providing a higher level of libido, sex drive, and an emotional high.

The testosterone to estrogen ratio would improve, reducing effects of excess estrogen. Insulin signaling is reduced. The body becomes less in an inflammatory state.

The person feels better, if not feels a high from the initial treatment with testosterone.

----

Over time, however, with increased dopamine signaling, dopamine receptor production is reduced back to a normal amount. Dopamine, as the reward signal, the feel good signal, can't be elevated for a prolonged period of time excessively, without problems occurring. It no longer becomes a reward signal if it is elevated for a prolonged period of time. Tolerance, through receptor reduction, occurs.

After the initial high, other problems also occur.

Exogenous testosterone suppresses testicular thyroid releasing hormone production. This reduces thyroid hormone production, undoing the initial increase in free thyroid hormone that testosterone caused. If there is hypothyroidism in the first place, this exacerbates that problem.

If there are other neurotransmitter, hormone, cytokine signaling problems or metabolic-nutritional problems outside of hypogonadism, these may complicate or undo what testosterone initially did.

If the man aromatizes testosterone to estrogen excessively, problems with excessive estrogen occur. If aromatization is not enough, then problems with too little estrogen occur. In either case, sex drive is impaired.

Thus, the hypogonadal man returns to Earth. And the initial high is lost.
__________________
-

Romeo B. Mariano, MD, physician, psychiatrist

[burlyman30]

Repped.

[BBG]

Repped.

x2. Great info J

[Jelisej]

Nice post from R. Marianco Adrenal Fatigue

I believe that when you seek to balance one neurotransmitter/hormone system, you have to also examine and balance the rest. They are all closely connected in their functions. From a mental health point of view it is important to optimize functioning in the neurotransmitter/hormone systems involved in reproduction (e.g. estrogens, testosterone, progesterone), adrenals (e.g. cortisol, DHEA, norepinephrine, epinephrine, dopamine, etc.), thyroid, pancreatic (e.g. insulin), besides the brain-involved neurotransmitter/hormone systems.

For example, in order for the thyroid hormone activity to function, adequate serotonin is necessary.

One of the important functions of testosterone is to limit adrenal activity - essentially to quell the stress response so that it does not rage on uncontrollably. Testosterone both causes a reduction of ACTH production from the pituitary, and directly reduces adrenal activity - both reducing the production of cortisol. Testosterone, by also increasing brain dopamine production, causes a reduction in norepinephrine production from the locus ceruleus. Norepinephrine is a signal for stress.

A high cortisol is one indicator of the amount of stress a person is experiencing and is trying to cope with - unless one is dealing with an adrenal disease state such as Cushing's Syndrome. Another would be high norepinephrine levels.

If anything, I think the best ways to reduce such stress include: 1) behavioral and environmental interventions to reduce stress, 2) increasing serotonin to help provide a buffer against the perception of stress - i.e. things hurt emotionally less, 3) optimizing testosterone level to control the adrenal stress response. When these don't work, other measures - often other psychiatric medications - are used. Improving the brain's ability to produce GABA, for example, is one of the alternatives - GABA being an inhibitory neurotransmitter than can help induce calmness - which is modulated using anxiolytic and other medications.

I am not sure that limiting adrenal output is necessarily the best thing to do because that also limits a person's ability to generate energy and get the body ready to respond to stress. The adrenal glands are like a car's transmission, where the brain is the engine. If the transmission is regulated, then the cars ability to accelerate when needed may be compromised. I think it would be better to reduce the stresses that necessitate increased adrenal output in the first place - before the adrenals fatigue.

Adrenal fatigue is a highly important condition to treat. It is a very common condition in our highly stress-filled lives. Adrenal fatigue is like having a transmission that is broken or is stuck in neutral. Pressing the accelerator pedal accomplishes nothing - which is what people with adrenal fatigue feel - the inabilitiy to generate energy on-demand.

Adrenal fatigue is most easily determined using saliva tests of DHEA and Cortisol levels done multiple times in one day. This is more sensitive than the blood tests. Adrenal fatigue can be evidenced also by low DHEA, low Cortisol, low progesterone levels. Hypothyroidism often occurs with Adrenal fatigue - possibly from the resulting impairment in production of neurotransmitters necessary for thyroid function, such as serotonin.


Adrenal Thread
Note: guy with nick "Swale" is J. Criesler, also endocrinologist

[Jelisej]

I like the way how Dr. marianco explains things so that everyone can understand it- another interesting post:

Low SHBG and Estradiol by Dr. Marianco.

The most common cause of low SHBG is excessive insulin - i.e. insulin resistance. Insulin resistance in turn leads to a cascade of events which results other hormone imbalances such as low testosterone production, suboptimal thyroid hormone activity, adrenal fatigue, etc.

Factors which together in a balance determine SHBG are:
1. Anabolic hormones generally reduce SHBG. These include testosterone, DHEA, insulin, DHT, and growth hormone.
2. Thyroid hormone, Estrogens, and Progesterone (by increasing estrogen receptors/sensitivity), increase SHBG.

In the absence of insulin resistance, the most common other cause of low SHBG is a very high level of other anabolic hormones - most frequency high testosterone from TRT. Those who use anabolic steroids at high doses often drive their SHBG to near zero.

When total testosterone is between 650 to 1000 ng/dl, and a person still has zero sex drive, I would look for other causes for sexual dysfunction - e.g. other hormone, neurotransmitter, or immune system problems.

Raising SHBG does not necessarily increase the risk for Alzheimer's disease. It is important to keep in mind the factors which lead to the risk of Alzheimer's disease.

Insulin resistance (i.e. excessive insulin levels) causes low SHBG. It also greatly increases the risk of Alzheimer's disease because it results in a higher level of inflammatory cytokine production (Cytokines are the chemical messengers of the immune system). It is the inflammation which is one of the underlying factors which leads to Alzheimer's disease.

SHBG level is most often a signal of the overall status of multiple hormone levels. The balance may give an indication of whether one is in an pro-inflammatory state or anti-inflammatory state - with inflammation leading to disease such as Alzheimer's disease, heart disease, strokes, cancer, etc. Some hormones such as some estrogens and insulin can lead to inflammation leading to illness. And other hormones such as the androgens (except DHT), growth hormone, and thyroid hormone, can lead to an antiinflammatory state, reducing the risk for illness. The balance determines the person's risk for illness.

What estradiol level is best for any individual often needs to be determined by trial and error. It is unique for each individual. Most do best around 30 pg/ml. But some do best at lower and higher levels. For example, I have a 65 y.o. patient with a total testosterone of 840 ng/dl and an estradiol of 47 pg/ml. He's having the time of his life - able to make love numerous times each night - after more than a decade of having no sex. The estradiol level works for him without side effects. Some may do better with much loser levels of estradiol - the response is highly individualistic.

Even with low SHBG - which is difficult to correct since it depends on the balance of so many hormones - when the other hormones and neurotransmitters are optimized, sex drive and the ability to have an erection can often return.

When total testosterone is supraphysiologic - i.e. over 1000 ng/dl - problems with libido and erections may occur. Testosterone increases dopamine in the brain in order to increase sex drive, reduce depression, give pleasure to activities. The problem is that dopamine is a very fragile neurotransmitter/hormone in its effects. Too high a dopamine level can cause tolerance to dopamine. This is similar to how one can develop tolerance to drugs such as cocaine and amphetamines which increase dopamine levels in the brain to cause their high. This can lead to the loss of libido when high testosterone levels are maintained for long periods of time.

Conversely, when one is deprived of testosterone (and hence dopamine) for long periods of time due to hypogonadism, one can get a high during the first few weeks of testosterone treatment since the brain becomes supersensitive to dopamine when it has been deprived of it (e.g. making more dopamine receptors to pick up the weaker dopamine signals). Unfortunately, as the brain then gets use to the higher dopamine levels, it will develop some tolerance, and libido will drop off - though we often wish that hopefully a good amount remains.

[Jelisej]

Continued, this part is bit debatable:

Free Testosterone will be determined by how much albumin is present to bind to testosterone (weakly bound testosterone), and how much SHBG is present to bind to testosterone (strongly bound testosterone). Albumin production is fairly stable and difficult to change without severe illness present. The albumin concentration is primarily determined by hydration - with dehydration increasing its level. SHBG is modified by multiple hormones: increased by thyroid, estrogens, progesterone; lowered by testosterone, DHT, DHEA, growth hormone, insulin; and is modified up or down by some medications, etc.

Is Free Testosterone a good measure of testosterone activity to determine whether nor not to adjust the testosterone dose? Not really.

First, Free Testosterone not a reliable test.

Secondly, and more importantly, it is also determined by multiple factors. It is more a measure of the sum of these factors than of testosterone activity itself.

For example, if there is too much estrogen, free testosterone can be lower since SHBG will be higher. If there is too little thyroid hormone, free testosterone can be higher. If there is insulin resistance (i.e. too much insulin), free testosterone will be higher. And so on. Thus, what is being measured by free testosterone? Certainly much more than testosterone activity itself. Therefore, it is difficult to say determine what needs to be adjusted to optimize function if free testosterone is used as the primary measure.

If anything, high or low free testosterone indicates there is a good chance that other hormonal imbalances (besides testosterone) are also occurring which need to be assessed and addressed - e.g. hypothyroidism, insulin resistance, high estradiol levels, etc.

Testosterone activity is determined by the sum of free testosterone's activity, weakly bound testosterone's activity (which has partial activity), and SHBG- bound testosterone activity (testosterone has signaling activity to SHBG receptors when bound to SHBG). Thus, Total testosterone comes closest to describing testosterone activity for clinical decision-making purposes for testosterone dosing.

One can also add DHT's activity (as some practitioners do) but one has to be careful since DHT can counteract testosterone's activity when DHT is too high.

How can one decide that the testosterone dose is too high or too low?

Using total testosterone, the TRT decisions become very simple:

1. The goal of TRT is getting the average total testosterone to at least 650 ng/dl (midrange on a reference scale from 300-1000 ng/dl).

2. If any problems remain, then it is due to other neurotransmitter/hormone/cytokine imbalances or excessive testosterone dose (i.e. supraphysiologic total testosterone).

These two constitute a rule of thumb - determined by the individual patient's circumstance - some patients need a lower, some patients need a higher dose of testosterone. However, no matter what the dose, realize that other imbalances in the body's information processing system (i.e. the sum of the nervous system, endocrine system, and immune system activities) may be present and need to be addressed.

Whether the total testosterone level over time is flat (as with pellets and usually alcohol-based gels) or with peaks or valleys (e.g. with testosterone injections, oil-based creams) is determined by the route of administration and the person's half-life for testosterone (and the ester if injections are used). Whether a flat or peak/valley testosterone time-curve is preferred depends on what a person best responds to.

Given how large an overlap there is between the symptoms of testosterone deficiency, thyroid hormone deficiency, cortisol deficiency, insulin resistance/diabetes, etc., it is important to look at the other hormones for a solution if total testosterone is at a good level.

How much estradiol (E2) is made depends a lot on how high total testosterone becomes and how much aromatase activity is present.

HCG use increases the production of aromatase - increasing estradiol production.

High testosterone doses (such as injections given once every two weeks), results in long-lasting supraphysiologic levels of estradiol. A solution in this case is to use smaller and more frequent doses of testosterone (such as by going to a twice a week injection - rather than larger once a week or once every two week injections). The lower peak testosterone levels resulting from more frequent injections reduces the exposure to aromatase, resulting in smaller estradiol levels. At the extreme, testosterone pellets usually have the least problems with estradiol. Of course, using Arimidex can also reduce estradiol.

[Jelisej]

Estrogens and aromatase inhibitors

Question and answer by Dr. Mariano:

Q: When it comes to brain health and estrogens and treating your male patients with aromatase inhibitors (that need them), what sort of estradiol levels do you try to reach in the effort to balance brain and body support from estrogen vs the common side effects such as gynecomastia, edema, etc?

A:Something not too high and not too low. Achieving this is complicated.

Generally, when using pg/mL for estradiol and ng/dL for testosterone, there is often going to be around a 20:1 to 30:1 ratio between testosterone and estradiol in men who don't have hypogonadism. This gives me a range where I can predict the estradiol level from a given testosterone level during treatment. When estradiol is below a 20:1 ratio to testosterone, it may be in excess.

Another technique is to simply chose absolute levels to target for estradiol during treatment.

Note that "estrogen" side effect such as gynecomastia and edema vary a lot in occurrence with men at each level of estradiol. Some have gynecomastia, nipple sensitivity, etc. at low estradiol levels. Some have no effect at high estradiol levels.

When Estradiol goes too low in a male, frequently sexual dysfunction and loss of competitive drive may occur. This is one marker for excessive dosing of an aromatase inhibitor. However, whether or not there is going to be such a negative effect depends on other signals and metabolism.

The sensitivity of each male to estradiol's effects will vary with the levels of other hormones, signals, and metabolic-nutritional status. For example, the estrogen signal, itself, may need adequate progesterone to stimulate the production of estrogen receptors. If hypothalamic-pituitary adrenal dysregulation is present, the estrogen signal is attenuated and symptoms of low estrogen may occur at higher levels. Additionally, thyroid hormone levels increase SHBG levels. The higher the SHBG, the higher the estradiol but less is free to function. Thus the estradiol signal is reduced despite the higher level. Once the other signal and metabolic-nutritional problems are addressed and signaling optimized in the other systems, the male may not have as large a negative effect from estradiol as prior to addressing the other problems first.

Thus each male treated needs to be considered individually in regard to the targets of treatment. Even with some guidelines, being flexible in approach necessary.