Subcutaneous vs. Intramuscular Testosterone: Do Delivery Methods Affect Blood Health and Hematocrit Risk?

[madman]

* 100 patients were identified as first-time TRT users, with 50 in the subcutaneous group and 50 in the intramuscular group. There was no significant difference in age, pre-TRT testosterone levels, pre-TRT hematocrit levels, or post-TRT hematocrit levels. There was a significant difference in post-TRT testosterone levels, with intramuscular TRT having a higher post-therapy level (p=0.02; Table 1).


* There is no significant difference in post-TRT hematocrit levels between intramuscular and subcutaneous TRT. However, intramuscular TRT did have significantly higher post-therapy testosterone levels compared to subcutaneous TRT.




Freeman, S1; Pohl, D1; Du Comb , W1

1 - Lahey Hospital and Medical Center


Introduction

A known side effect of testosterone replacement therapy (TRT) for men with hypogonadism is polycythemia. Elevated hematocrit levels can have negative consequences on overall health and can increase one’s risk of developing cardiovascular disease, organ damage, or blood clots. Polycythemia can also cause several symptoms, such as headaches, fatigue, or dizziness. With the development of different routes of testosterone administration, the question of how these various testosterone delivery methods might differentially impact hematocrit levels should be considered.


Objective

To determine whether intramuscular and subcutaneous TRT differ in their effects on hematocrit levels.


Methods

A retrospective chart review was completed of all patients who had received subcutaneous or intramuscular TRT at our institution since 2019. Patients were excluded from the study if they did not have pre- or post-TRT testosterone or hematocrit levels, were younger than 18, or were on a previous TRT regimen prior to starting subcutaneous or intramuscular TRT. Statistical significance was determined using an unpaired t-test for all variables.


Results

100 patients were identified as first-time TRT users, with 50 in the subcutaneous group and 50 in the intramuscular group. There was no significant difference in age, pre-TRT testosterone levels, pre-TRT hematocrit levels, or post-TRT hematocrit levels. There was a significant difference in post-TRT testosterone levels, with intramuscular TRT having a higher post-therapy level (p=0.02; Table 1). A subgroup analysis of patients with hematocrit greater than 45 was also performed, which had no significant difference in hematocrit levels pre- or post-TRT. A linear regression was performed, showing no association between change in testosterone levels and change in hematocrit levels after TRT in either the intramuscular or subcutaneous cohort (R2= 0.0007 and R2= 0.0159).


Conclusions

There is no significant difference in post-TRT hematocrit levels between intramuscular and subcutaneous TRT. However, intramuscular TRT did have significantly higher post-therapy testosterone levels compared to subcutaneous TRT. This data allows providers and patients to choose delivery methods for TRT based on factors aside from hematocrit levels, such as patient preference or cost.




Figure 1. Mean levels of testosterone and hematocrit pre and post testosterone replacement therapy differentiated based on administration route

 

[Cataceous]

This study should not be used to suggest that subcutaneous administration is less effective than intramuscular. First, free testosterone would be the more definitive measurement, and that was not used. Second, there's no mention of dosing. Then there's the hint of bias in the total testosterone measurements, with the SC cohort starting out with lower numbers. If the groups were starting out with similar average free testosterone then the implication would be that the SC cohort has lower SHBG, artificially driving down total testosterone. Interestingly, we see that the ratios of pre- and post-TRT levels are the same, which is to say that each group tripled total testosterone. If both groups had similar doses and saw similar or limited changes in SHBG then this is evidence that increases in free testosterone were similar for both.

 

[FunkOdyssey]

This study should not be used to suggest that subcutaneous administration is less effective than intramuscular.

You know I'm going to do that anyway despite the preemptive warning.

Then there's the hint of bias in the total testosterone measurements, with the SC cohort starting out with lower numbers. If the groups were starting out with similar average free testosterone then the implication would be that the SC cohort has lower SHBG, artificially driving down total testosterone. Interestingly, we see that the ratios of pre- and post-TRT levels are the same, which is to say that each group tripled total testosterone. If both groups had similar doses and saw similar or limited changes in SHBG then this is evidence that increases in free testosterone were similar for both.

Let's test out this explanation with some numbers. Lets say the IM group with a baseline total T of 230.4 ng/dL had an SHBG of 40 nmol/L, and a baseline free T of 3.9 ng/dL. If you think the SC group had a lower SHBG and a similar free T, then with a total T of 187.9 ng/dL, their SHBG would have been 28 nmol/L.

The SHBG levels would have probably changed a bit on treatment, but for the sake of this exercise, let's assume they remained the same. The IM group with a Total T of 683.2 ng/dL now has a free T of 13.6 ng/dL, and the SC group with 548.6 ng/dL now has a free T of 12.9 ng/dL (a bit lower).

But wait, it gets worse. Assuming trough lab testing, subcutaneous injection SHOULD always be higher than intramuscular injections when everything else is equal, because of the slower release of testosterone from the subq depot. The fact that the subq group was not higher, but indeed lower at trough, would suggest a significantly lower testosterone AUC across the interval between injections.

Of course, if that were true, it becomes difficult to explain why hematocrit would be higher on the SC injections. Maybe that is just a random finding? At the least, it undercuts one of the major advantages SC injections are supposed to have over IM (lower HCT).

In addition to free T measurements, E2 levels for each group would be very interesting to see. Is there a full text of this paper available? Where did you find this @madman?

 

[Cataceous]

You know I'm going to do that anyway despite the preemptive warning.



Let's test out this explanation with some numbers. Lets say the IM group with a baseline total T of 230.4 ng/dL had an SHBG of 40 nmol/L, and a baseline free T of 3.9 ng/dL. If you think the SC group had a lower SHBG and a similar free T, then with a total T of 187.9 ng/dL, their SHBG would have been 28 nmol/L.

The SHBG levels would have probably changed a bit on treatment, but for the sake of this exercise, let's assume they remained the same. The IM group with a Total T of 683.2 ng/dL now has a free T of 13.6 ng/dL, and the SC group with 548.6 ng/dL now has a free T of 12.9 ng/dL (a bit lower).

But wait, it gets worse. Assuming trough lab testing, subcutaneous injection SHOULD always be higher than intramuscular injections when everything else is equal, because of the slower release of testosterone from the subq depot. The fact that the subq group was not higher, but indeed lower at trough, would suggest a significantly lower testosterone AUC across the interval between injections.
...

Interesting that we used almost identical numbers to test this. I had SHBG of 40 and 27 nMol/L, FT of 13.6 and 13.1 respectively, the latter well within margins of error. Of course I also searched for the full text, but so far even the abstract only shows up on this page.

It would be problematic if these are trough values with relatively infrequent injections. Then I would fall back to suggesting other sources of bias or errors, such as SC injection site leakage, different doses, etc. The Xyosted trials were more rigorously controlled and provided comparable areas-under-the-curves for IM and SC.