Dr. Mariano is a well respected Physician in the TRT vertical. I've read many of his papers and I consider him one of the best. The paper below describes why men get that initial "high" when they start a new TRT protocol after being low for a prolonged period of time. There are also other points of interest in this paper as well. This is very good read fellows...enjoy!
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If a male is hypogonadal for an extended period of time, then the first exposure to testosterone repla***ent 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.
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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 repla***ent. 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.
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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.
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Romeo B. Mariano, MD, physician, psychiatrist
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Originally Posted by Parsons51
joke..........I read a similar article recently, not as in depth but basically stating that dopamine was responsible for the good feeling men got in that first little while after starting TRT. Interesting stuff for sure.
