TRT

[Jelisej]

TRT and Thyroid- more testosterone more thyroid needed

More post by Dr. Mariano:

Usually, when I start testosterone replacement therapy (TRT), I also have to be ready to adjust thyroid hormone because exogenous testosterone can reduce thyroid signaling.

Changing one signal (as in testosterone) causes multiple downstream signaling changes in other systems. As long as one is ready to make the adjustments to thyroid hormone signaling and other signaling systems with TRT (such as estrogen signaling, adrenal signaling, nervous system, immune system, metabolism, nutrition, etc.), then one can avoid some complications with TRT, such as anxiety, fatigue, hypertension, insomnia, body aches, etc.

Off the top of my head, there are several possible ways TRT can reduce thyroid hormone signaling, including the following:

1. Exogenous testosterone suppresses testicular testosterone production AND testicular thyroid releasing hormone (TRH) production. This reduces brain TSH production, lowering thyroid hormone production from the thyroid gland.

2. Exogenous testosterone may reduce liver production of thyroid binding globulin. This reduces the half-life of thyroid hormone. This leads to a reduction in available thyroid hormone.

3. Exogenous testosterone can lead to a simultaneous conversion of testosterone to estradiol. The increase in estradiol can increase liver production of thyroid binding globulin. This can lead to a reduction in free thyroid hormone levels (Free T3, Free T4). This then reduces thyroid signaling.

4. Exogenous HCG (human chorionic gonadotropin) not only increases testicular production of testosterone and sperm but also increases aromatase enzyme production. The increase in aromatase enzyme can then lead to an increase in estradiol production from testosterone. This (as noted above) can lead to a reduction in thyroid signaling.

5. Exogenous testosterone can suppress ACTH (adrenocorticotropic hormone) production from the brain. And it can directly suppress adrenal cortical activity, including cortisol production. This can then lead to an increase in norepinephrine production, then immune system inflammatory signaling. This can then shift thyroid metabolism so that T4 is converted to reverse T3 (the waste product pathway) instead of being converted to T3 (the active thyroid hormone). This can reduce both T4 levels and T3 levels, leading to a reduction in thyroid signaling.

When possible, I usually prefer to consider first optimizing thyroid signaling, adrenal function, immune system function, nervous system function, metabolism and nutrition, to allow a smoother transition to testosterone replacement therapy.

There are times when adding testosterone simultaneously while addressing the other systems is important to help break some positive feedback loops between systems that contribute to illness. For example, high insulin/insulin resistance/diabetes, obesity, inflammatory signaling, stress/norepinephrine signaling, and lower testosterone production can be involved in multiple positive feedback loops which can cause significant illness. Adding testosterone when it is low in such a person can help unravel the self-perpetuating signaling loops that keep a person ill.

- - - Updated - - -

Continued:
Most often, men will have to increase the dose of thyroid hormone after starting TRT. I have yet to see a need to lower thyroid hormone in men who start TRT.

Off the top of my head, one possible mechanism by which testosterone can lead to an increase in thyroid hormone is if there is significant inflammatory cytokine signaling resulting in a shift of T4 metabolism to Reverse T3 rather than T3.

If exogenous testosterone helps reduce inflammatory cytokine signaling, it can then help reduce reverse T3, leading to an increase in T3 production from T4.

On the other hand, increased inflammatory signaling can also lead to an increase in sympathetic nervous system norepinephrine production, i.e. stress signaling. This may then increase deiodinase enzyme production, increasing T4 to T3
conversion.

If Testosterone reduces stress/norepinephrine signaling - and testosterone is usually a very calming signal unless a lot is transformed to estradiol - then the addition of exogenous testosterone would negate norepinephrine's increase in
T3 production.

This can possibly negating the gain from the above antiinflammatory effects of testosterone. This would lead to a wash in thyroid change from the addition of testosterone via these two mechanisms.

The sum of the above and other pathway influences on thyroid hormone would determine whether or not thyroid hormone increases or decreases with the addition of exogenous testosterone.

In my experience, usually, exogenous testosterone generally reduces thyroid hormone signaling. The population that I may see, however, may be different from that seen by other physicians.

[Jelisej]

Question: Thanks for the detailed answer Dr. Mariano. And does higher and higher
estradiol bind more thyroid, making you more hypo?

I'm thinking if estradiol is brought down with DIM or arimidex, it would then
free up your bound thyroid, meaning you'd lower your thyroid dose. Yes? No

Answer:
It not that estradiol binds more thyroid hormone. Estradiol increases liver production of thyroid binding globulin which binds thyroid hormone, leaving less in the free form.

Reducing estradiol vis DIM or Arimidex works to a certain point, then worsens the situation.

Lowering estradiol would reduce thyroid binding globulin production. This increases free thyroid hormone. However, if thyroid binding globulin is reduced excessively, then the half-life of thyroid hormone is reduced. This results in an increased breakdown of thyroid hormone, leading to a reduction in total thyroid hormone.

Arimidex also has a limit in reducing estradiol. In some men, the body may compensate by increasing production of estradiol via alternative pathways when its production via the aromatase enzyme is reduced excessively. Thus there may be a ceiling in reducing estradiol after which the body uses other pathways to produce estrogen. Also other estrogens may be produced when estradiol is reduced excessively. One can't also reduce estradiol excessively before the liver compensates by increasing cholesterol production.

It is a matter of balance. Estrogens are monitored more closely by the brain than testosterone in determining production of the reproductive hormones.

[Jelisej]

Bit more about: SHBG
SHGB (Sex Hormone Binding Globulin):

Let's look at what influences SHBG:

Increases SHBG:
Estrogens (particularly Estradiol)
Progesterone (by increasing Estrogen receptors)
Thyroid Hormone (particularly Hyperthyroidism)
Liver Disease
Anorexia, Starvation
Hypoglycemia (low insulin)

Reduces SHBG:
Insulin (and insulin resistance)
Testosterone
Growth Hormone
DHEA
Other Androgens
Obesity
Hypothyroidism
Excessive Cortisol (Cushing's Syndrome or Disease)
Progestins (such as by blocking progesterone's effects)

The primary purpose of a binding protein such as SHBG is to prolong the life of testosterone in the body. Otherwise, with a half-life of 10-100 minutes - testosterone would be almost totally eliminated from the body within 50 minutes to 8.3 hours without constant production or frequent application of testosterone.

The quickest way to increase SHBG is to treat a person with T3 (Cytomel) or to a lesser extent Armour Thyroid, when optimizing thyroid hormone signaling. This increases SHBG production from the liver. Optimizing thyroid signaling first is important to set the stage for subsequent testosterone treatment. Doing so helps correct low SHBG.

Low SHBG is one of many reasons testosterone levels are so low in diabetes type 2. When SHBG is low due to insulin resistance/diabetes type 2 and high insulin level, treatment with testosterone helps reduce insulin resistance. Over several months time, SHBG self-corrects as other metabolic improvements with testosterone treatment occur such as loss of belly fat. Of course, in the presence of diabetes type 2, one of the first things to do is to optimize thyroid hormone and treat the insulin resistance with medications such as Metformin or Actos. This would help improve SHBG and would set the stage for testosterone treatment, minimizing problems that can occur with testosterone treatment - such as anxiety, irritability, fatigue, excessive estrogen, etc.

Low SHBG also occurs in inflammatory diseases (such as rheumatoid arthritis, etc.) - where Interleukin 1 beta reduces SHBG production. I generally assess for the presence of immune system problems since they are often at the root of mood disorders. Reducing pro-inflammatory signaling would help correct their role in reducing SHBG.

SHBG is important but usually it is self-corrected by addressing more important problems - such as hypothyroidism, diabetes, chronic inflammatory illness - prior to testosterone replacement.

When it does become a significant problem is when it is too high - such as with high dose T3 treatment in cases of peripheral thyroid resistance. When SHBG is high, a normal 100 mg a week dose of testosterone cypionate can achieve blood levels past 1500 ng/mL. A concern at that level when coupled with high SHBG is that the lower free testosterone levels may become a significant factor in reducing the effects of testosterone. SHBG bound to testosterone does have signaling function on its own - what it does is unclear - but it is interesting to speculate that if the testosterone-bound SHBG signal is too high, perhaps it may inhibit libido.

[Jelisej]

Effect of hormone therapy on activity of other hormones




Copy of effect on hormone therapies.jpg

[Jelisej]

Stress, adrenal insufficiency, HPA downregulation and TRT
Originaly post written by R. Mariano

To summarize some issues a lot (since the actual mechanisms can be mind-bogglingly complex):

Chronic or traumatic stress may lead to hypothalamic-pituitary-adrenal axis dysregulation (the term which I believe is more accurate to use than the term "adrenal fatigue"), HPA dysregulation for short.

HPA dysregulation leads to lower production of adrenal cortex signals/hormones. This includes lower cortisol and/or DHEA, progesterone, pregnenolone, testosterone, estradiol, or aldosterone.

The primary signal for stress is norepinephrine. Norepinephrine is in a positive feedback loop with corticotropin releasing hormone. This positive feedback loop is interrupted by cortisol signaling. To increase norepinephrine, the brain has to also reduce production of some or all of the control signals that suppress norepinephrine signaling. These include reductions in serotonin, dopamine, GABA, etc.

Stress (particularly if it is a perceived threat), may lead to an increase in pro-inflammatory cytokine signaling from the brain and from the immune system (which is directly innervated by neurons of the sympathetic nervous system - the primary norepinephrine-releasing neurons of the nervous system). Stress may also lead to an increase in histamine signaling from brain mast cells. These changes lead to an activation of the immune system. These changes in large excesses may lead to an increase in inflammatory processes. The loss of anti-inflammatory signaling - which includes cortisol, DHEA, progesterone and testosterone - exacerbates these pro-inflammatory changes.

Excessive pro-inflammatory cytokine signaling may trigger automatic defensive programs in the brain. Defensive programs may induce behavioral changes including depressed mood, loss of interest or motivation in activities, loss of enjoyment from activities, social isolation, changes in sleep including the desire to sleep excessively.

There may be a loss of energy from excessive pro-inflammatory cytokine signaling. The actual mechanisms of the loss of energy are not clear. I currently speculate that perhaps there may be impaired brain astrocyte conversion of thyroxine (T4) to triiodothyronine (T3) - which leads to a hypothyroid central nervous system with a euthyroid body (as in Alzheimer's disease). Perhaps the increase in pro-inflammatory cytokines is one of the signaling problems leading to HPA dysregulation, aside from excessive norepinephrine signaling. However, other regulatory systems may also be involved - such as the opiate signaling systems (which also involve dopamine signaling).

HPA dysregulation, from whatever cause, leads to a loss of energy. The loss of energy production, however, under some circumstances. These circumstances include bipolar disorder and attention deficit/hyperactivity disorder with hyperactivity. In these cases, norepinephrine production is an effective signal for energy.

Nutrition plays a large role in the development of HPA dysregulation. Omega 3 vs. Omega 6 balance helps determine the balance between inflammation and anti-inflammation. Various nutrients (such as the B-vitamins, fat soluble vitamins, magnesium, etc) are cofactors for many of the processes involving signal production. Vitamin A and D are generally anti-inflammatory signals. Vitamin D reduces insulin resistance (which helps the body tolerate low blood sugar from impaired cortisol signaling), increases serotonin and dopamine production. Vitamin A helps regulate the sensitivity to various hormones/signals such as thyroid hormone.

The other endocrine signaling systems such as the reproductive system are in play. Testosterone helps reduce norepinephrine, increases dopamine production. It also suppresses adrenocorticotropin releasing hormone and directly inhibits adrenal cortex activity - this may be significant depending on the sum of signaling interactions and problems a person has. Estrogen acts similarly to a monoamine oxidase inhibitor - thus increasing serotonin, norepinephrine and dopamine (but serotonin primarily). Estrogen in relative excess may be pro-inflammatory, reduces free thyroid hormone. Thyroid hormone signaling loss is compensated by an increase in norepinephrine production with simultaneous activation of adrenal cortex signals. Over time, however, this compensation may fail as HPA dysregulation occurs. Insulin, glucagon, the incretins, etc. also have a role. Insulin, itself, is pro-inflammatory. Growth hormone has a calming effect and is anti-inflammatory. Etc. etc. etc. etc.

The entry point of all these processes is stress. This is represented primarily by norepinephrine signaling. However histamine (from brain mast cells) and pro-inflammatory cytokines (from brain microglia) are also involved in the process. Stress induces responses that are ostensibly designed to improve survival. The problem is that in the modern world, these responses may be dysfunctional instead.

===

Given the complexity of the interactions involved, a single intervention may or may not work. Which direction an intervention goes depends on the sum of the changes that occur as a result of that intervention. In psychiatry, the usual answer to a question is "It depends."

Stress is the entry point. Environmental and behavioral interventions would clearly help with few downsides.

Low dose testosterone may help, particularly in women, by helping to reduce norepinephrine and increasing dopamine signaling, and helping to reduce pro-inflammatory signaling. Low dose testosterone would not help in men since it may do nothing or it would suppress endogenous production of testosterone, leading to lower overall testosterone levels. Men would need replacement doses of testosterone. Testosterone, however, may also worsen adrenal cortex function depending on a person's susceptibility to this. In men, exogenous testosterone treatment also suppresses testicular thyroid releasing hormone production, leading to a loss of thyroid hormone production, which then leads to an increase in norepinephrine production. This is why in certain men, even if hypogonadal, testosterone treatment is intolerable. The rest of the system has to be optimized before testosterone treatment can be done.

Tamoxifen (I would prefer this to Clomiphene due to the visual changes that can occur with Clomiphene) is a weak estrogen. This blocks the stronger estrogens from being sensed by the brain. This then causes the brain to release more Luteinizing Hormone to stimulate testosterone production, leading to estrogen production. The increase in testosterone would have the effects listed previously. The problem is that Tamoxifen also blocks estrogen. This leads to lower estrogen signaling activity. Estrogen helps control norepinephrine by increasing serotonin and dopamine production. Estrogen is also needed to improve sensitivity to testosterone by increasing testosterone receptor production. Estrogen is also important in generating energy, motivation, drive, competitiveness, sex drive (libido). Estrogen (particularly in women) is important for neuron growth and memory. The loss of estrogen signaling, depending on the balance with testosterone, may lead to negative effects. If testosterone production is driven high enough, then perhaps this would improve things overall. This is particularly true in men. However, in women, this may not occur and destabilization of the system and dysfunction may occur instead. This is why many women do not like treatment with Tamoxifen or Arimidex for breast cancer.

Cortisol treatment alone may or may not work. Cortisol treatment in sub-replacement doses helps because it helps break the norepinephrine-CRH positive feedback loop. Cortisol also acts in the brain to improve concentration/focus by allowing the brain to ignore emotionally distracting memories or information. Cortisol also is the most important anti-inflammatory signal that reduces immune system activity. Cortisol triggers gluconeogenesis - helping improve blood sugar production. etc. etc. Thus it can be a useful component of treatment. However, Cortisol treatment alone also suppresses adrenal cortex activity. Thus, there is also a loss of pregnenolone, progesterone, DHEA, testosterone, estradiol, aldosterone, etc. If this loss is large enough, then the person may be worse off than without treatment. Since the majority of these other signals are calming, help control norepinephrine, are anti-inflammatory signals, a significant loss may cause the opposite intended effect of cortisol treatment. This is where some people become more tired, get "brain fog", become more anxious, etc. on cortisol monotherapy.

A systematic treatment has to be considered to address the multiple issues that invariably occur, contributing to HPA dysregulation. Single modality treatments may help - particularly in those people who don't have large problems in the rest of their system. But often, in more severe cases, they don't. A systemic approach would then be needed. I would count the person who responds to monotherapy as very fortunate.

[burlyman30]

Great post. Reps inbound.

[Jelisej]

Charts on how long it takes to feel effect from TRT:
Onset of effects of testosterone treatment ... [Eur J Endocrinol. 2011] - PubMed - NCBI


Some more interesting charts showing different TRT plans and comparing them:

The Androgen-Deficient Aging Male: Current Treatment Options

[Jelisej]

Adrenal insufficiency and insomnia

Adrenal insufficiency is linked to insomnia in two ways:

1. If your cortisol drops too low during the night your blood sugar drops too. Your body compensate by releasing adrenaline as an emergency measure to mobilize more sugar. This has the effect of waking you in an instant. This can be reduced by eating high protein snack before retiring e.g. sardines, nuts of high quality protein shake.

2.In early stages of adrenal fatigue cortisol levels tend to rise and if they are high at midnight they can energise you and keep you awake. Phosphorylated serine can be used to lower cortisol at these times due to its ACTH dampening effect.



Complete text with few more bits:
Adrenal Fatigue Chelation livingnetwork.co.za

[Jelisej]

HCG AND HCG MONOTHERAPY

Few words on HCG and HCG monotherapy and some effect of HCG, again I'll use posts written by Dr Romeo Marianco, as they are quite simple and easily to understand and also I'll post extract commenting on Dr Shippens methods. Some posts are bit old so and in meantime few bits have changed like dosages etc...

Dr. Shippen has found that a typical treatment course for three weeks is best for determining those individuals who will respond well to HCG treatment. It is administered daily by injection 500 units subcutaneously, Monday through Friday for three weeks. The patient is taught to self administer with 50 Unit insulin syringes with 30 gauge needles in anterior thigh, seated with both hands free to perform the injection.

Testosterone, total and free, plus E2 (estradiol) are measured before starting the protocol and on the third Saturday after 3 weeks of stimulation (he claims that salivary testing may be more accurate for adjusting doses). Studies have shown that subcutaneous injections are equal in efficacy to intramuscular administration.

By measuring the effect on his HCG protocol on total testosterone, he identifies candidates that require testosterone replacement versus those who just require having their testicles “awaken” with HCG to produce normal testosterone. I am yet to see any data that substantiates his approach, however.

Here is how he determines Leydig (testicular) cell function:
1. If the HCG protocol causes less than a 20% rise in total testosterone he suggests poor testicular reserve of Leydig cell function (primary hypogonadism or eugonadotrophic hypogonadism indicating combined central and peripheral factors).
2. 20-50% increase in total testosterone indicates adequate reserve but slightly depressed response, mostly central inhibition but possibly decreased testicular response as well.
3. More than 50% increase in total testosterone suggests primarily centrally mediated depression of testicular function.

He then offers these options for treatment for patients depending on the response to HCG and patient determined choices.
1. If there is an inadequate response, then replacement with testosterone will be indicated.
2. The area in between 20-50% will usually require HCG boosting for a period of time, plus natural boosting or “partial” replacement options.
Dr. Shippen believes that full replacement with testosterone is always the last option in borderline cases since improvement over time may frequently occur as the testicles’ Leydig cell regeneration may actually happen. He claims that much of this is age dependent. Up to age 60, boosting is almost always successful. In the age range 60-75 is variable, but will usually be clear by the results of the stimulation test. Also, disease related depression of testosterone output might be reversible with adequate treatment of the underlying process (depression, obesity, alcohol, deficiency, etc.) He claims that this positive effect will not occur if suppressive therapy is instituted in the form of full testosterone replacement.

3. If there is an adequate response of more than 50% rise in testosterone, there is very good Leydig cell reserve. HCG therapy will probably be successful in restoring full testosterone output without replacement, a better option over the long term and a more natural restoration of biologic fluctuations for optimal response. But I am yet to see any data on long term use of HCG used in this approach! (I invite researchers to do such studies)

4-. Chorionic HCG can be self-administered and adjusted according to response. In younger, high output responders (T > 1100ng/dl), HCG can be given every third or fourth day. This also minimizes estrogen conversion. In lower level responders (600-800ng/dl), or those with a higher estradiol output associated with full dose HCG, 300- 500 units can be given Mon-Wed-Fri. At times, sluggish responders may require a higher dose to achieve full testosterone response.
He claims that later as Leydig cell restoration occurs, a reduction in dose or frequency of administration may be later needed.

Mariano on HCG mono:
HCG (chorionic gonadotropin) increases testosterone production. Generally, in monotherapy for hypogonadism, it is used in doses to reach an adequate target level of testosterone production - e.g. 650 ng/ml.

HCG also stimulates aromatase enzyme production. This increase the production of estradiol from testosterone. One of the problems in using HCG for testosterone replacement therapy is that excessive estradiol may result in some men - even in lose doses such as in Dr. Crisler's protocol (250 IU twice a week).

Estradiol is a stronger signal for reducing LH (lutenizing hormone) production than testosterone. The brain, in a way, places more importance on measuring estrogen than testosterone (which also requires progesterone in order to be sensed optimally by the brain).

The amount of estradiol formed from exogenous testosterone treatment depends on existing aromatase enzyme activity (which, could be increased, for example, in men with larger amounts of belly fat (visceral fat).

In both HCG monotherapy and exogenous testosterone treatment, the target level of testosterone is the same - generally about 650 ng/ml (halfway between the reference range of 300-1000, as per Endocrine Society guidelines for the treatment of hypogonadism).

Which form of therapy suppresses LH more will depend on which induces estradiol production more. This is difficult to predetermine since each man is different in aromatase enzyme activity and susceptibility to increase aromatase from HCG. Some men do very well on HCG monotherapy and do not have excessive estradiol production.

All things being equal, however, I would expect HCG monotherapy to cause more LH suppression (?) since there would be more estradiol formed from increased aromatase enzyme production. Exogenous testosterone alone would not increase aromatase enzyme production.

Here I can see a difference from Shippens opinion (who talks about Leydig cells increase), as he mentions desensitation.
HCG is one option in maintaining testicular function and testosterone production.

Whether or not it would keep testosterone levels more stable is questionable. It probably does NOT given the much longer half-life of testosterone cypionate and enanthate (about 7 days on average) compared to testosterone (10-100 minutes).

I would generally prescribe a total of 3000 IU a week divided into 3 or 7 doses. This would give a testosterone level comparable to Testosterone Cypionate at 100 mg a week.

"Natural" is a questionably used term. HCG is not natural in men. The use of an aromatase inhibitor is also not natural. Nor is injecting something "natural". But these options may be necessary or useful to improve function. One primarily needs to assess risk vs. benefit to help make their decision on the course of treatment.

At a certain age, such as in one's fifties, the testes become less sensitive to HCG. At this time, HCG will stop working and alternatives would have to be used. Too high a dose of HCG would hasten testicular insensitivity to HCG

Few more interesting points:
One patient had excessive progesterone production, as an example of a different expression pathway, and normal estradiol production, in response to HCG treatment.

Perhaps, by stimulating steroid hormone formation, it stimulates precursors to testosterone, such as progesterone, which can also go through different pathways to reach estradiol rather than testosterone. For example, in the testes, progesterone is the main precursor for testosterone. Progesterone production has to ramp up for testosterone production. But progesterone can also be shunted to 17 hydroxy-progesterone to androstenedione to estrone to estradiol. Thus it would not just be aromatase enzyme that is stimulated, but all the other steroid pathyway enzymes.

Note that the production of estradiol is the primary reason for LH production. The hypothalamus and pituitary are much more sensitive to estradiol levels than testosterone levels. Having testosterone, in a way, is a side effect.

In development, if the fetus with XY chromosomes is insensitive to testosterone, it automatically develops into a female - though without ovaries or a uterus.

He here says that more frequent (HCG) injections are more better; I think we all agree to that, also some research suggest that HCG half-life may be shorter than previously tought (33 hours vs 68/72).
Whatever method for testosterone replacement is used, when testosterone is kept at a stable and not excessive level, estradiol production is minimized. Thus with HCG, the more frequent the dosing, the better. With testosterone cypionate injections, the shorter the half-life for testosterone cypionate, the shorter the intervals should be between injections.


HCG and thyroid function
Dr Mariano:
HCG (chorionic gonadotropin) can potentially affect thyroid hormone activity.

1. HCG can act like TSH (thyroid stimulating hormone), increasing thyroid hormone production from the pituitary. In pregnant women, HCG levels are high enough to raise thyroid hormone by up to 50% over the non-pregnant state. In testosterone replacement therapy, the amount of HCG used may not be enough to significantly increase thyroid hormone production directly since small doses are used.

2. HCG can act like LH (Luteinizing hormone), stimulating testosterone production from the testes, when used in hormone replacement therapy. It will also stimulate TRH (thyroid releasing hormone) production from the testes. This would in turn increase TSH then thyroid hormone production from the pituitary.

HCG, however, also stimulates the production of aromatase enzyme from the testes. This will increase conversion of testosterone to estradiol. Estradiol, in turn, would increase thyroid binding globulin from the liver. This would reduce free thyroid hormone levels, reducing thyroid hormone signaling activity.

The sum of these actions would determine whether or not HCG would improve thyroid hormone signaling activity.

Dr J. Criesler's white papers on HCG:
AN UPDATE TO THE CRISLER HCG PROTOCOL
By John Crisler, DO
In my paper “My Current Best Thoughts on How to Administer TRT for Men”, published in A4M’s 2004/5 Anti-Aging Clinical Protocols, I introduced a new protocol where small doses of Human Chorionic Gonadotrophin (HCG) are regularly added to traditional TRT (either weekly IM testosterone cypionate or daily cream/gel). The reasons and benefits of this protocol are as follows, along with a new improvement I wish to share:

Any physician who administers TRT will, within the first few months of doing so, field complaints from their patients because they are now experiencing troubling testicular atrophy. Irrespective of the numerous and abundant benefits of TRT, men never enjoy seeing their genitals shrinking! Testicular atrophy occurs because the depressed LH level, secondary to the HPTA suppression TRT induces, no longer supports them. It is well known that HCG—a Luteinizing Hormone (LH) analog—will effectively, and dramatically, restore the testicles to previous form and function. It accomplishes this due to shared moiety between the alpha subunits of both hormones.

So, that satisfies an aesthetic consideration which should not be ignored. Now let’s delve into the pharmacodynamics of the TRT medications. For those employing injectable
testosterone cypionate, the cypionate ester provides a 5-8 day half-life, depending upon the specific metabolism, activity level, and overall health of the patient. It is now well-established that appropriate TRT using IM injections must be dosed at weekly intervals, in order to avoid seating the patient on a hormonal, and emotional, roller coaster. Adding in some HCG toward the end of the weekly “cycle” compensates for the drop in serum androgen levels by the half-life of the cypionate ester. Certainly the body thrives on regularity, and supplementing the TRT with endogenous testosterone production at just the right time—without inappropriately raising androgen OR estrogen (more on that later)—approximates the excellent performance stability of transdermal testosterone delivery systems for those who, for whatever reason or reasons, prefer test cyp.

But there’s another metabolic reason to employ this protocol. The P450 Side Chain Cleavage enzyme, which converts CHOL into pregnenolone at the initiation of all three metabolic pathways CHOL serves as precursor (the sex hormones, glucocorticoids and mineralcorticoids), is actively stimulated, or depressed, by LH concentrations. It is intuitively consistent that during conditions of lowered testosterone levels, commensurate increases in LH production would serve to stimulate this conversion from CHOL into these pathways, thereby feeding more raw material for increased hormone production. And vice versa. Thus the addition of HCG (which also stimulates the P450scc enzyme) helps restore a more natural balance of the hormones within this pathway in patients who are entirely, or even partially, HPTA-suppressed.

It is important that no more than 500IU of HCG be administered on any given day. There is only just so much stimulation possible, and exceeding that not only is wasteful, doing so has important negative consequences. Higher doses overly stimulate testicular aromatase, which inappropriately raises estrogen levels, and brings on the detrimental effects of same. It also causes Leydig cell desentization to LH, and we are therefore inducing primary hypogonadism while perhaps treating secondary hypogonadism. 250IU QD is an effective, and safe, dose. After all, we are merely replacing that which is lost to inhibition.

In my previous report I recommended 250IU of HCG twice per week for all TRT patients, taken the day of, along with the day before, the weekly test cyp injection. After looking at countless lab printouts, listening to subjective reports from patients, and learning more about HCG, I am now shifting that regimen forward one day. In other words, my test cyp TRT patients now take their HCG at 250IU two days before, as well as the day immediately previous to, their IM shot. All administer their HCG subcutaneously, and dosage may be adjusted as necessary (I have yet to see more than 350IU per dose required).

I made this change after realizing that the previous HCG protocol was boosting serum testosterone levels too much, as the test cyp serum concentrations rise, approaching its peak at roughly the 72 hour mark. The original goal of supporting serum androgen levels with HCG had overshot its mark.

Those TRT patients who prefer a transdermal testosterone, or even testosterone pellets (although I am not in favor of same), take their HCG every third day. They needn’t concern themselves with diminishing serum androgen levels from their testosterone delivery system. These patients will, of course, notice an increase in serum androgen levels above baseline.

While HCG, as sole TRT, is still considered treatment of choice for hypogonadotrophic hypogonadism by many , my experience is that it just does not bring the same subjective benefits as pure testosterone delivery systems do—even when similar serum androgen levels are produced from comparable baseline values. However, supplementing the more “traditional” TRT of transdermal, or injected, testosterone with HCG stabilizes serum levels, prevents testicular atrophy, helps rebalance expression of other hormones, and brings reports of greatly increased sense of well-being and libido. My patients absolutely love it. As time goes on, we are coming to appreciate HCG as a much more powerful--and wonderful--hormone than previously given credit.

[Jelisej]

Dr Shippens graph for calculating free testosterone from Total testosterone and SHBG

Dr Shippen chart 1.jpg