My name is Todd “IncreaseMyT” Thomas. I have been working for increasemyt.com for over a decade. My main responsibility is patient management for men and women who are on hormone replacement therapy. Over the last decade I have had the pleasure of helping men and women maintain successful healthy long term hormone replacement protocols. Through this experience I have had a direct vantage point of the doctor patient relationship with over 3,000 clients and have been able to view over 10,000 lab results of men and women that had undertaken hormone replacement therapy. Through my experience and the relevant peer reviewed clinical literature I will paste, I will attempt to solve this issue once and for all.
The million dollar question. This question has been debated endlessly since before my time in the TRT (Testosterone Replacement Therapy) field, 15 years ago.
For years the notion has been growing that more frequent injections leads to more stable testosterone levels in the blood, and that makes a lot of sense right? So of course, it is the first logical solution that comes to ones mind when trying to decipher the vast amount of user reports spread across the world wide web.
But is this really the best way? Do people feel “better” on a more frequent injection schedule? Are there any long term consequences to injecting frequently?
I am going to cover all of this and more in the following argument. Full disclosure, I think frequent injections of esterified testosterone are a plague on the TRT community. But first, let’s start with how a man produces testosterone naturally or what we in the field refer to has eugonadal testosterone. In contrast to when we supplement testosterone this would be considered exogenous testosterone, or testosterone from outside the body.
Eugonadal Hormone Production in Normal Men
Testosterone and other hormones are balanced by what is known as the negative feedback loop. Simply put, this means your body can calculate the amount of a certain hormone in the blood at a certain time and send signals to organs in the body to either increase the level of that hormone or decrease it. This is usually done both by converting that hormone to another hormone and limiting (suppressing) the production of the hormone or increasing (stimulating) the hormone.
This very complex system in the human body is known as the Hypothalamic Pituitary Testicular Axis (HPTA) and it regulates your sex, adrenal and thyroid hormones.
HPTA
In a normal healthy male most of our testosterone is made at night. Men who were sleep restricted showed a significant depression in total testosterone (TT) levels. Once testosterone is made and sent out into the blood 98% of it gets attached to Sex Hormone Binding Globulin (SHBG). The 2% that remains is your free testosterone (FT). This means it is free and unbound and available to attach to the androgen receptors (AR). This is what gives you the androgenic effect, the activation of the AR, not the testosterone.
So in simpler terms, testosterone is merely a messenger signal and SHBG is a preservative and the major function is to preserve testosterone levels in the blood so that the body can use them later, understand this is completely different from preserving testosterone in the muscle tissue with a depot injection of esterified testosterone.
So although Total Testosterone (TT) levels only fluctuate 10% on any given day, the fluctuation of SHBG combined with the fluctuation of TT means your free testosterone can rise and fall multiple times throughout the day quite substantially. This is called a diurnal rhythm, which at the end of the day just means really complex system that produces and regulates sex hormones throughout a 24 hour period. You are going to have a really hard time catching this on a blood test too. A blood test is just a snapshot of what is going on in the blood at a single point in time. So if we really wanted to find out how much free testosterone levels fluctuated in a 24 hour period we would have to poke someone 10 times a day, and that is just not realistic. So there is not much literature on this.
Diurnal rhythm can be affected by many things, such as a lack of sleep, something you ate or drank, how much exercise you got. All these things play a role in the amount of TT and the amount of FT that you have.
So although daily injections of esterified testosterone will keep your levels more “stable” they do not match eugonadal production at all. Far from it. This is one of the arguments that the daily injection believers use, that they are “matching their bodies natural production”. Instead they are taking their levels way up to the top of range or above, and leaving them there with daily injections. Offering androgen stimulation no relief. The human body was not meant to have all of its androgen receptors turned on all the time.
This is a terrible way to do TRT because you are saturating your receptor fields. What do I mean by that? Testosterone has a dose response relationship with the human body. This means it has a certain effect on the body which is dependent on the dosage. The higher you go, the less positive effect you get per mg and the more negative affect you will get per mg. Low testosterone shows a inverse relationship to high testosterone although the relationship is not linear. In other words there is a sweet spot in regard to androgen receptor activation, just like there is a sweet spot on a baseball bat when you are hitting home runs. How do I know this to be true? We can look at the medical breakthrough made by Dr Morgentaler at the University of Harvard to understand this relationship:
The Saturation Model and the Limits of Androgen-Dependent Growth
For 70 years testosterone has been the black sheep of the family. Doctors and medical professionals were scared to death to touch it. We chemically castrated men to erase their testosterone when they had end stage prostate cancer only to find out later that optimal levels of testosterone reduce your risk of aggressive prostate disease by 50%. So it is no surprise that many physicians are confused about the positive and negative effects associated with testosterone replacement therapy. This is where Dr Morgentaler’s research changed the way we view testosterone forever. Dr. Morgentaler suggested that it was not testosterone that caused prostate cancer, he even later went on to inject testosterone in 4 men with end stage prostate cancer and it was a complete success, they achieved regression. So how did Dr Morgentaler prove that testosterone was not the responsible party? First let’s take a look at the cliff notes of his study from 2009:
So what does all this mean in a practical conversation? It means that although when men were injected with testosterone there was tissue growth in the prostate initially, once the saturation limit had been reached “the presence of additional androgen produces little effect”. So if we know that we can only get so much stimulation from testosterone, what happens to the rest? It gets converted to other hormones. So if there is only so much androgen receptor stimulation, is there really a point in taking our testosterone levels into or near supraphysiological range or more than what a person would be able to make naturally at their age? If you look at the above study in the image I posted, you can see it is noted that maximal AR binding occurs well within physiological range. The only other benefit to taking your levels this high is to get either positive or negative effects from excessive amounts of DHT and estradiol, these are both made out of the excess testosterone.
So let’s do a quick recap before I drop the bombshell. We can take testosterone to stimulate our androgen receptors, but there is a saturation limit to this effect and once we reach that the testosterone is either wasted or converted to DHT or E2.
Is it fair to guess that maybe this whole time, for 70 years, that elevated levels of E2 in conjunction with elevated levels of testosterone could have been the phantom culprit? Well of course it would make sense right, when women or men get breast cancer they are given meds that specifically reduce or block estradiol. If E2 didn’t play a role in tissue growth what would be the point of that?
The truth is we don’t know how all the exacts work here because we unfortunately do not have a cure for cancer at the moment. But if you ask me this literature does 2 things:
#1 Shows that testosterone has a saturation limit in terms androgen receptor activity.
#2 Insinuates that way back in 1938 Charles Huggins may have mistakenly identified testosterone as the culprit in prostate cancer growth, when in actuality the high testosterone levels converting to E2 was the phantom culprit.
So this makes a great argument as to why you do not need supraphysiological levels when on hormone replacement therapy for long periods, but we have not addressed the issue of saturation in a clinical setting.
My argument is that daily injections of esterified testosterone produces levels that are consistently near the top or higher than what a person can produce and maintain naturally. This varies by age but will have a net negative effect on how you feel when on a long term hormone replacement therapy program if you are consistently near the top for your age group.
We see this in our client base when they switch to really frequent injections but I want to go over some literature below that suggests the same thing.
No Positive Effect on Insulin Sensitivity
One of the main reasons a saturation doses of T can make a man not feel as good is because of insulin sensitivity. Although optimal levels of T have a positive effect on insulin response, saturating your receptors for long periods of time will have the opposite effect, a negative response on insulin sensitivity. This is shown in the literature below:
Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men
As you can see in men with low testosterone levels, although increasing total testosterone levels was associated with increased insulin sensitivity in diabetic men, increased free T levels either had no relationship or had a clinically insignificant relationship. What is the difference here? The difference is that consistently high Free T levels have a negative impact on insulin sensitivity.
I know what you are thinking, the study says free T levels had no effect and I am saying it has a negative effect why am I saying this? These men are diabetic so the individuals insulin sensitivity cannot get any worse. So the negative effect cannot be shown, they are already on the floor.
So at this point, maybe I haven’t convinced you that consistently high free T levels reduces insulin sensitivity, but I hope we can both agree that there is a optimal level of TT and FT and therefore a ratio that is required to get a positive effect on insulin response.
Increased Risk of Polycythemia, or high HCT
Over the last decade working for increasemyt.com I have had the pleasure of communicating with our clients about blood work and one common theme exists, consistently high FT levels leads to a increase in in your hematocrit the majority of the time. This simply means that the viscosity of your blood is changing as it is becoming thicker. To an extent, this is not a bad thing, after all this is why athletes sleep in hyperbaric chambers, to increase the amount of oxygen in the blood so that endurance increases. If someone has had a testosterone deficiency for a long period, a positive increase is probably going to be welcomed, as this is one of the main reasons testosterone replacement therapy makes you feel so much better. But remember our blood is becoming thicker, can it get too thick? This in and of itself has also became a hotly contested debate. This is because although people that have or are at risk for a myocardial infarction (heart failure or impairment) have been shown to have polycythemia or high HCT, no one has suffered a stroke from TRT induced high HCT. This means there is no correlation between high HCT and cardiovascular risk and noone has actually had a stroke related to TRT induced high HCT. A thorough review in the New England Journal of Medicine did not reveal a single case of TRT induced polycythemia that leads to a myocardial infarction, although experts who participated in the study stated that this does not mean the risk does not exist, and that a HCT over 55% suggests that treatment should be discontinued until HCT is under control. I am not going to delve any deeper into this specific issue, whether or not high HCT from taking too much testosterone increases your risk of heart problems is not relevant to my argument today.
For this article, we are going to focus on whether or not frequent injections increase your chance of developing polycythemia or a consistently high HCT. As I mentioned earlier I have seen this in a clinical setting personally, but I would like to focus on the literature below:
Erythrocytosis Following Testosterone Therapy.
These studies suggest that higher serum (TT) trough levels of testosterone increase the risk that you will develop polycythemia, or high HCT when injecting testosterone. Trough just means where your levels bottom out, or the point right before you do your next injection.
When you inject a esterified testosterone each one has a certain half-life. So if I inject esterified testosterone and create a testosterone depot in the muscle tissue or subcutaneous tissue the testosterone will be cleaved from the ester and released into the blood based on the half-life of each specific formulation that you use. So if we look at testosterone cypionate we know we are injecting testosterone that is attached to the cypionate ester. This acts as a time release according to its half-life which is generally accepted to be roughly 6 days. So if you inject this type of ester every single day then your trough level average is going to be higher than if you did once weekly injections and remember this is not how the body operates normally and the above study suggests that at increases your risk for polycythemia. Consistent injections of esterified testosterone keep your TT and FT high all the time increasing your risk of polycythemia and negating any positive effect on insulin sensitivity.
Carotid Intima-Media Thickness (CIMT) Positive Negated By High E2
Once levels reach saturation some of your testosterone is converted to E2, it is simply spillover. So we mentioned earlier that we suspect E2 to be the phantom culprit in the prior confusion of whether or not testosterone gives you prostate cancer but is it healthy for the heart? It has long been suspected that increased E2 can lead to high blood pressure or water retention, especially edema in the ankles but there is not a lot of literature confirming this. This is because the sparse literature on testosterone replacement therapy is all done in a very conservative manor. In the clinical setting I have witnessed either increase in blood pressure or edema to be associated with high levels of E2, but naysayers say it is not actually E2 that is the culprit, and that there is no reason to correct your estradiol levels on TRT if they get too high. We wholeheartedly disagree with this absurdity.
Although the subjects in the observational study below were not on hormone therapy, we can extrapolate that increased levels of E2 even in the presence of testosterone can negate or even worsen the positive effects testosterone replacement therapy has on CIMT:
So this is very interesting, this study suggests that men who had normal T levels but high E2 were associated with a increase carotid intima-media thickness.
CIMT refers to the carotid arteries in your neck and how thick they are. Testosterone replacement therapy has been shown to reduce thickness of these arteries in peer reviewed observational studies on men with angina or Coronary Artery Disease (CAD). If we look at the context most men were on gel or injections of T only once every 2 weeks. So FT, TT and E2 are not high in these subjects and patients levels at the time of testing were well within physiological range.
The study suggests that this positive effect is negated, and thickness gets worse when E2 levels are high and in the presence or normal testosterone levels, but it also showed that a increase in E2 in men with CAD actually showed a reduction in CIMT. So what gives why are there 2 different results here?
The group that already had CAD showed positive effect from “higher” levels of E2 not “high levels” of E2. So what the researchers are saying here is that men who already had low testosterone and low E2 benefited from a increase in E because they had deficient hormone levels to begin with. So just like testosterone there is a specific optimal range at which E2 benefits you health wise. The literature suggests that in “normal men” meaning they had normal levels of testosterone, that high E2 was associated with a increase or negative impact in CIMT. The study does not mention supraphysiological range so there is no reason to believe that E2 ever reached levels above threshold, but based on a diurnal rhythm and the fact we know that testosterone and therefore E2 fluctuates daily, we can extrapolate that consistent higher levels of E2, in the presence of normal levels of testosterone increases your risk of increased CIMT and negates the positive effect testosterone therapy has on your heart when properly managed.
You have made it this far so looks like it is a good read. Please ask any questions about the article specifically in the forum. If you have a hormone deficiency and you would like more information on how to become a client of mine and a patient of increasemyt.com please shoot me an email directly at info@increasemyt.com Here is to a happy, healthy and successful long term hormone replacement therapy program.
Cheers!!!
Todd “IncreaseMyT” Thomas
