Difference between daily IM vs daily SubQ?

Been on for about 10 months and have tried multiple frequencies, administration sites, and dosages.

All of these trials were based on the need to control elevated H&H. The one that did the trick in mitigating it was daily subcutaneous injections totaling 70mg/week. Labs for this protocol were done about 12 weeks after switching.

Levels sit at 830 ng/dL total, and above the ref range with free. All other relevant markers are great. The issue was that over the last few months, I've been feeling more and more "off." Libido has been down, I've been somewhat lethargic, and I've experienced some weird emotional blunting.

Tried switching back to IM, but this time with daily injections about a week ago and have noticed a substantial change and resolution to the issues mentioned above.

So my question is, when you're on a daily injection protocol, is there that much difference between IM and SubQ? Mostly wondering about peaks, valleys, and overall stability in serum concentration levels. I plan on doing bloods in 8 weeks to see if it shows anything (CBC, TT, FT, E2, etc). Ultrasensitive and LC/MS, of course. On that note, is 8 weeks a little overkill for protocol swap from SubQ to IM? I know it's important for the reverse.

Thanks in advance!

I'm not sure how much this will help you. I do daily injections. I inject in six locations shallow IM in VG, shoulders and Sub-Q and love handles. I've been doing daily injections for about 8 years.

When I say six locations I mean right and left side.

Vince said:

I'm not sure how much this will help you. I do daily injections. I inject in six locations shallow IM in VG, shoulders and Sub-Q and love handles. I've been doing daily injections for about 8 years.

When I say six locations I mean right and left side.

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Was actually wondering if anyone did a mix of IM and subQ. Have never done VG, only delts, stomach fat, and quads. What size needle do you use for your VG? I've used 1/2 30g insulin syringes for everything.

For my first 2 years of trt, I only injected in my shoulders twice a week. Then I went to daily injections and started rotating them. I use a 29g half inch syringe, every third day I inject both HCG and testosterone in the same syringe.

SH3P said:

So my question is, when you're on a daily injection protocol, is there that much difference between IM and SubQ?

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Some men see substantially lower total and free testosterone with subq and higher E2, while some men do not. The percentage affected negatively is not clear. The only study to capture this effect was one of the Xyosted studies comparing xyosted to enanthate IM - other studies have not replicated it or even shown lower E2 with subq injection. Doesn't change our observed reality.

Some men feel much better injecting IM, which sometimes correlates with differences in hormone levels like I mentioned above. However, sometimes the numbers are similar on paper, and yet the person still somehow feels better with IM. You might be in that category and will find out when you get your lab results.

The pharmacokinetics should be somewhat (like maybe 20-30%) different between IM and subq, with a lower peak, higher trough, and longer half-life with subq.

While not often acknowledged, differences (if any) between IM and SubQ can also be related to your body fat. I’m at about 12% (with very little fat) and can easily inject into muscle with a 1/2” insulin needle.

SH3P said:

Been on for about 10 months and have tried multiple frequencies, administration sites, and dosages.

All of these trials were based on the need to control elevated H&H. The one that did the trick in mitigating it was daily subcutaneous injections totaling 70mg/week. Labs for this protocol were done about 12 weeks after switching.

Levels sit at 830 ng/dL total, and above the ref range with free. All other relevant markers are great. The issue was that over the last few months, I've been feeling more and more "off." Libido has been down, I've been somewhat lethargic, and I've experienced some weird emotional blunting.

Tried switching back to IM, but this time with daily injections about a week ago and have noticed a substantial change and resolution to the issues mentioned above.

So my question is, when you're on a daily injection protocol, is there that much difference between IM and SubQ? Mostly wondering about peaks, valleys, and overall stability in serum concentration levels. I plan on doing bloods in 8 weeks to see if it shows anything (CBC, TT, FT, E2, etc). Ultrasensitive and LC/MS, of course. On that note, is 8 weeks a little overkill for protocol swap from SubQ to IM? I know it's important for the reverse.

Thanks in advance!

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What do your hemoglobin and hematocrit numbers look like on daily injections vs your previous protocol frequency?

FunkOdyssey said:

Some men see substantially lower total and free testosterone with subq and higher E2, while some men do not. The percentage affected negatively is not clear. ...

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This premise is still on shaky ground regarding testosterone, given that the rigorous data show comparable areas-under-the-curves—and no plausible mechanism for losing testosterone, except via injection site leakage. I'll grant there's more ambiguity with estradiol. One hypothesis is that the shape of the free T curve affects the aromatization rate.

MegaTurd said:

What do your hemoglobin and hematocrit numbers look like on daily injections vs your previous protocol frequency?

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120mg M/W/F SubQ
HGB: 18.8
HCT: 56.7%

70mg ED SubQ

50 Days in- the numbers above had stalled, with my HCT coming down more than HGB.

100 Days in

HGB: 17.7
HCT: 53.2%

Hard to know which played a role in the reduction, since I went ED at the same time as a reduced dose. I'd assume the reduction in dose made the most difference, but sharp peaks are still thought to play a role, so I'd assume frequency played at least some part in it. Then there's the time variable where my body has been reaching homeostasis over time, which has eliminated initial side effects one-by-one.

Cataceous said:

This premise is still on shaky ground regarding testosterone, given that the rigorous data show comparable areas-under-the-curves—and no plausible mechanism for losing testosterone, except via injection site leakage.

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AI to the rescue with plausible mechanisms:

Yes, delivering drugs into the lymphatic system via subcutaneous (SC) injections can lead to differences in drug absorption and bioavailability compared to intramuscular (IM) injections. These differences might result in a reduced amount of the active drug reaching systemic circulation, effectively causing a "loss" of some of the drug when compared to IM administration. Here are some mechanisms that could explain this:

1. Delayed Absorption and Reduced Bioavailability:

Slower Lymphatic Flow: The lymphatic system transports substances more slowly than the bloodstream. Drugs delivered SC may take longer to reach systemic circulation because they rely on lymphatic uptake, leading to delayed onset of action.

Variable Absorption Rates: SC injections can result in more variable absorption rates due to differences in subcutaneous tissue thickness and lymphatic drainage between individuals and injection sites.

2. Enzymatic Degradation in Lymphatic Tissue:

Metabolic Enzymes: The lymphatic system contains enzymes that can metabolize drugs before they reach the bloodstream. This pre-systemic metabolism can reduce the amount of active drug available.

Immune Cell Interaction: Drugs entering the lymphatic system may interact with immune cells (like macrophages), which could metabolize or sequester the drug, decreasing its bioavailability.

3. Protein Binding and Sequestration:

Binding to Lymph Proteins: Drugs may bind to proteins within the lymph, reducing the free concentration of the drug available for absorption into the bloodstream.

Sequestration in Lymph Nodes: Some drugs may become trapped in lymph nodes, especially if they are designed to target or are recognized by immune cells, leading to decreased systemic availability.

4. Inflammatory Responses:

Local Inflammation: The introduction of drugs and excipients into the lymphatic-rich SC tissue might trigger local inflammatory responses. Inflammation can alter lymphatic function and permeability, potentially affecting drug absorption.

Immune Activation: Activation of the immune system might lead to the production of cytokines and other factors that can influence drug metabolism and transport.

5. Differences in Drug Formulation Absorption:

Depot Formation: IM injections often create a depot in muscle tissue, allowing for a more sustained and controlled release of the drug into the bloodstream.

Solubility Factors: The solubility of the drug and its excipients in lymph versus blood can affect how much of the drug is absorbed and how quickly.

6. Phagocytosis by Immune Cells:

Drug Uptake by Macrophages: In the lymphatic system, macrophages and other phagocytic cells might engulf drug particles, leading to decreased amounts of free drug entering systemic circulation.

7. First-Pass Metabolism Avoidance:

Lymphatic Delivery: While lymphatic delivery can bypass hepatic first-pass metabolism, it introduces the drug to other metabolic processes within the lymphatic system that might reduce its bioavailability.


Comparison with IM Injection:

Rich Blood Supply: Muscle tissue has a more abundant blood supply than subcutaneous fat, allowing for quicker and more efficient absorption of the drug directly into systemic circulation.

Less Enzymatic Activity: Muscle tissue generally has lower levels of metabolic enzymes that could degrade the drug before it enters the bloodstream.

Consistent Absorption: IM injections typically result in more predictable pharmacokinetics due to the uniformity of muscle tissue compared to the variability of subcutaneous tissue.

Conclusion:

Delivering drugs into the lymphatic system via SC injections can result in a reduced amount of active drug reaching systemic circulation due to factors like slower absorption rates, enzymatic degradation, immune system interactions, and sequestration within lymphatic tissue. This potential "loss" of drug compared to IM injections could explain why some individuals experience different therapeutic outcomes between the two administration routes. Understanding these mechanisms is important for optimizing drug delivery methods to achieve the desired therapeutic effects.

FunkOdyssey said:

AI to the rescue with plausible mechanisms:
...

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I've played this game with AI before. Ask leading questions and it will tell you what you want to hear. But once you start challenging it for making things up you can easily make it change its "mind". In this case there is specific data that contradicts the hypothesis. The arguments about absorption rate go nowhere, because the dose is eventually absorbed. There is evidence of a somewhat longer effective half-life with SC vs IM. Statements about enzyme levels changing the metabolic clearance rate require supporting evidence. Existing articles are saying that metabolism of testosterone occurs restrictively in the liver.

Would a 5/16 needle be long enough for IM in delt for an average sized man?

Cataceous said:

I've played this game with AI before. Ask leading questions and it will tell you what you want to hear. But once you start challenging it for making things up you can easily make it change its "mind". In this case there is specific data that contradicts the hypothesis. The arguments about absorption rate go nowhere, because the dose is eventually absorbed. There is evidence of a somewhat longer effective half-life with SC vs IM. Statements about enzyme levels changing the metabolic clearance rate require supporting evidence. Existing articles are saying that metabolism of testosterone occurs restrictively in the liver.

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Previously on this forum, I provided evidence that the esterases to remove esters from testosterone are present throughout the body, including interstitial fluid in fat tissue, which I felt was a plausible explanation for the reduced T/E2 ratios sometimes observed with SC injections. I also speculated that the immune system may somehow destroy or interact with testosterone in such a way to reduce T levels with SC injection, which was an idea AI came up with independently today.

It has happened too many times to too many people at this point to not be a thing, in SOME cases. It's only anecdotal data, but the numbers of anecdotes are overwhelming - you will run into people complaining of lower levels with SC anywhere and everywhere testosterone is discussed on the Internet.

As always, I will add that SC works wonderfully for many people, so no one should be discouraged if its their favored injection method.

FunkOdyssey said:

Previously on this forum, I provided evidence that the esterases to remove esters from testosterone are present throughout the body, including interstitial fluid in fat tissue, which I felt was a plausible explanation for the reduced T/E2 ratios sometimes observed with SC injections. ...

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As I recall, @madman offered a rebuttal to this idea.

FunkOdyssey said:

...
It has happened too many times to too many people at this point to not be a thing, in SOME cases. It's only anecdotal data, but the numbers of anecdotes are overwhelming - you will run into people complaining of lower levels with SC anywhere and everywhere testosterone is discussed on the Internet.
...

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Here's the biggest problem, though. These anecdotes have little meaning when area under the curve is not measured. If this really were a significant effect then it would show up in the clinical trials. Alternatively you'd have to acknowledge that "overwhelming" numbers are actually pretty small to have avoided detection.

Cataceous said:

As I recall, @madman offered a rebuttal to this idea.


Here's the biggest problem, though. These anecdotes have little meaning when area under the curve is not measured. If this really were a significant effect then it would show up in the clinical trials. Alternatively you'd have to acknowledge that "overwhelming" numbers are actually pretty small to have avoided detection.

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The anecdotes are trough measurements. The trough is supposed to be higher with SC than with IM injection. When the trough is instead lower, not by a little bit, but by 25%, 40%, 50%, you don't need to see the complete area under the curve to determine that the SC injection delivered less bioavailable testosterone. We don't know if it got eaten by a macrophage like pacman or what, but we can be sure it's not in your bloodstream.

This is reality, and if you are one of the people who respond in this way, your labs demonstrating lower SC bioavailability are far more meaningful than the couple of studies comparing SC to IM injection.

I hate to see YOU both doing this!

If I find time I will try to get the raw data of clinical studies. Meanwhile common to provide raw data in other fields of research but rare in clinical research..
Without knowing the studies you referred to, it's important to understand how to interpret statistics. I'm sure you do but that's 'far from common'. Like one member here recently wrote: at this state of TRT we are all 'lab rats'. What is lacking is fundamental research with the aim to explore, truly understand all relevant factors including outliers in order to explain individual responses as opposed to population based statistics (clinical studies).

E.g. see Fig.6 follow the reference 26

See Fig. 1
How well does the PK model fit the data?

Have seen a case study at TRT clinic where the PK looked very different having a rapid drop starting at around week 4. MDs wouldn't believe the patient reported symptoms, then they measured his levels every week. ... maybe far from common but it does happen.
Frequentist believe vs Bayesian reality? I don't know...

What would a scientist do vs most MDs attitude....

A couple of graphs from the TU pharmacokinetic study jump out at me. What occurs to me looking at the first one: there may be people out there actually absorbing SC better than IM, such that it cancels out noticeable differences when comparing average levels between larger groups of IM and SC injectors.

Still, you can see SC came out a bit worse even considering that:


On the T/E2 ratio effects of IM vs SC, I know I am on firmer ground, as this has even been documented in one of the Xyosted studies. They made no mention of the clinical significance of this massively different T/E2 ratio, but the data was presented nonetheless (Table 2 from the first study Seagal linked above):

FunkOdyssey said:

The anecdotes are trough measurements. The trough is supposed to be higher with SC than with IM injection. When the trough is instead lower, not by a little bit, but by 25%, 40%, 50%, you don't need to see the complete area under the curve to determine that the SC injection delivered less bioavailable testosterone. We don't know if it got eaten by a macrophage like pacman or what, but we can be sure it's not in your bloodstream.
...

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The trough is supposed to be higher, but it's more plausible that these individuals have unusually fast SC absorption than that these highly speculative mechanisms for testosterone disappearance apply. And that's assuming no injection site leakage. I have personally seen injection sites go through phases in which there's substantial leakage every time if site rotation is inadequate—and I'm using relatively minuscule volumes compared to most.

FunkOdyssey said:

...
This is reality, and if you are one of the people who respond in this way, your labs demonstrating lower SC bioavailability are far more meaningful than the couple of studies comparing SC to IM injection.

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I'll be waiting for those AUCs.

@Seagal:
Table 2 in particular. SC actually appears to have slightly better bioavailability than IM.

HSLD said:

Would a 5/16 needle be long enough for IM in delt for an average sized man?

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I tried using 5/16 for IM and the subjective results were not good. Did not compare well against 1/2".

On the larger issue of daily IM versus SQ, I certainly feel better with IM. However, I find it impractical to inject IM every day for years on end. I am low dose like yourself.

I have tried mixing IM with SQ, but my body did not seem to like the different absorption rates. And yes, after hundreds and hundreds of injections, there is no doubt in my mind that IM hits faster than SQ resulting in higher peak but lower trough. I assume average TT is more or less the same, but I don't care. Just go by feel and keep experimenting!