Intramuscular versus Subcutaneous Testosterone Injections: Effect on TT, hematocrit, E2, and PSA

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madman

Super Moderator
Comparison of Outcomes for Hypogonadal Men Treated with Intramuscular Testosterone Cypionate Versus Subcutaneous Testosterone Enanthate (2020)

Introduction
: Intramuscular testosterone cypionate (IM-TC) is the conventional treatment option for hypogonadal men with baseline serum total testosterone (TT) less than 300 ng/dL; however, significant peaks in testosterone cause adverse effects including polycythemia and a rise in estradiol (E2). Subcutaneous testosterone enanthate-autoinjectors (SCTE-AI) were designed with a lower testosterone peak-to-trough ratio of 1.8.

Objective: This dual-institutional study compared the TT, hematocrit (HCT), E2, and prostate-specific antigen (PSA) response to treatment with IM-TC versus SCTE-AI.

injections.jpg


Methods: 263 hypogonadal men were treated with testosterone replacement therapy (TRT) via IM-TC or SCTE-AI. TT, HCT, E2, and PSA levels were obtained at baseline and 6- to 12-weeks post-treatment. Significant differences in baseline and post-treatment levels were identified by univariate analysis. Linear regression models determined whether treatment modality was independently associated with post-TRT levels of TT, HCT, E2, and PSA.

Results: Patients treated with SCTE-AI were significantly younger, had lower baseline TT levels, and lower baseline E2 levels (Table 1). Post-TRT, the SCTE-AI cohort had significantly lower HCT and E2, while TT and PSA levels were not significantly different between the treatment arms. After adjusting for significant differences with linear regression, SCTE-AI was associated with a 14% greater increase in trough TT levels compared to IM-TC (p=0.027). Furthermore, SCTE-AI was independently associated with 41% and 26.5% lower post-therapy HCT (p<0.001) and E2 (p<0.001) levels, respectively, when compared to IM-TC. Neither TRT modality was associated with post-therapy elevation of PSA (p=0.691).

Conclusions: While IM-TC and SCTE-AI provide a significant increase in testosterone, SCTE-AI is associated with lower levels of post-therapy HCT and E2 compared to IM-TC after adjusting for significant covariates. SCTE-AI is an effective testosterone delivery system with a preferable safety profile over IM-TC.




Table 1. Clinical demographics and treatment outcomes of intramuscular testosterone cypionate (IM-TC) compared to subcutaneous testosterone enanthate-autoinjector (SCTE-AI).
 

IM-TC

SCTE-AI

    
 

n=188

n=114

    
 

mean (SD)

mean (SD)

p-value

   

Age

54.4 (13.4)

49.7 (10.5)

0.001

   

Pre-Therapy

      

TT

313.6 (263)

249.6 (113)

0.006

   

HCT

45.2 (4.2)

44.8 (3.4)

0.453

   

E2

30.4 (15.5)

25.3 (9.2)

0.004

   

PSA

1.4 (1.8)

1.1 (0.8)

0.072

   

Post-Therapy

      

TT

536.4 (295)

552.5 (207)

0.629

   

HCT

48.4 (4.4)

46.3 (3.8)

<0.001

   

E2

46.6 (25.9)

33.0 (15.4)

<0.001

   

PSA

1.3 (1.3)

1.2 (0.9)

0.565

   
       

TT: Total Testosterone; HCT: Hematocrit; E2: Estradiol; PSA: prostate-specific antigen
 
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Cataceous

Super Moderator
@readalot: Interesting results here w/respect to testosterone levels and HCT. The study seems to suggest that higher peaks—or time at higher levels—is driving HCT. This contradicts the hypothesis that more variation—with time spent at lower levels—is helpful. Do you agree with this interpretation? The SC group has higher troughs, so that's not doing it. And presumably average levels are similar between groups.
 

readalot

Active Member
@readalot: Interesting results here w/respect to testosterone levels and HCT. The study seems to suggest that higher peaks—or time at higher levels—is driving HCT. This contradicts the hypothesis that more variation—with time spent at lower levels—is helpful. Do you agree with this interpretation? The SC group has higher troughs, so that's not doing it. And presumably average levels are similar between groups.
Thanks for letting me know. I'll definitely be excited to read this study once I find it :).
 

madman

Super Moderator
Finally! The study we have been waiting for!. Thanks @madman

Can you post the reference please?


You heard it here first @myloyalty resides with one!




Comparison of Outcomes for Hypogonadal Men Treated with Intramuscular Testosterone Cypionate versus Subcutaneous Testosterone Enanthate (2020)
Screenshot (2670).png




Screenshot (2683).png
 

readalot

Active Member
@readalot: Interesting results here w/respect to testosterone levels and HCT. The study seems to suggest that higher peaks—or time at higher levels—is driving HCT. This contradicts the hypothesis that more variation—with time spent at lower levels—is helpful. Do you agree with this interpretation? The SC group has higher troughs, so that's not doing it. And presumably average levels are similar between groups.
Certainly at first glance the suggestion seems plausible from the results. But the reported TT levels are troughs as I read so are the IM guys really spending more time at lower levels? I'd be curious if the treatment effect is confounded with age. Clearly significant difference in age between the treatment groups. In the context of this paper, is there a lurking effect that may be a nonlinear function of age?


If you did an intragroup analysis of age vs Hct, would there be an significant relationship?

If you remove treatment modality from the analysis in table 2b, does age then appear significant? I would want to understand if age and treatment modality are correlated and hence making treatment modality appear to be the significant effect when in reality there's some older guys dragging on the IM group?

Finally troughs are similar between groups so presumably Cavg is higher for the IM group?

If you repeated the study and switched the groups to receive the other treatment what would happen?

I realize it would be hard to keep Cavg the same across groups so then at least control for age so there's no significant difference in age between groups since erythrocytosis susceptibility with TRT seems to be a function of age.
 
Last edited:

bennettjc

Member
This is very interesting. Thanks for posting!! What I would like to know is the frequency of injection for each group. The SubQ Test E group was almost certainly once a week because the "autoinjector" Test E group was clearly Xyosted. I do wonder about the more "old-school" IM group. Did they also get the old-school every two weeks IM treatment? Or was it once a week? Doubt that it was more than once a week because the ALL of the 6 or 7 urologists and endocrinologists I've seen can't get past once a week. I often tease them by saying "I know people who dose daily." Anyway.... I'm going to email one of the authors.
 

Cataceous

Super Moderator
Certainly at first glance the suggestion seems plausible from the results. But the reported TT levels are troughs as I read so are the IM guys really spending more time at lower levels? I'd be curious if the treatment effect is confounded with age. Clearly significant difference in age between the treatment groups. In the context of this paper, is there a lurking effect that may be a nonlinear function of age?
...
Perhaps because it's only a poster there are some important details missing, including precise protocols, times of lab work relative to injections, etc. If the reported TT values are troughs then that would seem to contradict the statement that "SCTE-AI was associated with a 14% greater increase in trough TT levels compared to IM-TC (p=0.027) (Table 2a)." I'm not up-to-speed on these statistical notations. Does Table 2a say that trough TT was 67 ng/dL higher in the SCTE-AI group? This would put trough TT for SCTE-AI at 546 ng/dL and for IM-TC at 479 ng/dL. However, the authors say this was "after adjusting for significant differences", which needs to be explained.

A five-year difference in average age seems kind of small to account for that kind of difference in HCT.
 

readalot

Active Member
Perhaps because it's only a poster there are some important details missing, including precise protocols, times of lab work relative to injections, etc. If the reported TT values are troughs then that would seem to contradict the statement that "SCTE-AI was associated with a 14% greater increase in trough TT levels compared to IM-TC (p=0.027) (Table 2a)." I'm not up-to-speed on these statistical notations. Does Table 2a say that trough TT was 67 ng/dL higher in the SCTE-AI group? This would put trough TT for SCTE-AI at 546 ng/dL and for IM-TC at 479 ng/dL. However, the authors say this was "after adjusting for significant differences", which needs to be explained.

A five-year difference in average age seems kind of small to account for that kind of difference in HCT.
Thanks for your comments. Take a look at the SD for age on the IM treatment group. There's some really older dudes in that group. Hard to make any conclusions unless we had the paper or raw data. I'm with you, I can't make the numbers for TT in Table 1 vs Table 2A quite work and I'd have to see how they are defining their multivariate regression terms and if they are normalizing their coefficients based on z-scores. Hilarious we are crucifying a poster presentation but this is cool data so we might as well get the conclusions right.
 

readalot

Active Member
This is very interesting. Thanks for posting!! What I would like to know is the frequency of injection for each group. The SubQ Test E group was almost certainly once a week because the "autoinjector" Test E group was clearly Xyosted. I do wonder about the more "old-school" IM group. Did they also get the old-school every two weeks IM treatment? Or was it once a week? Doubt that it was more than once a week because the ALL of the 6 or 7 urologists and endocrinologists I've seen can't get past once a week. I often tease them by saying "I know people who dose daily." Anyway.... I'm going to email one of the authors.
Great points. I didn't mention but I was assuming sub-Q group was definitely Xyosted as they (Antares) have been sponsoring a bunch of research in this arena. I was also assuming weekly dosing frequency and same dosage between groups [some of these papers titrate the dose (50, 75 or 100 mg weekly) to target Cavg in range over the course of the study]. But you are correct we don't know the details. If you are going to email the authors I'd be happy to participate in a "peer-review" if they are willing to share more details and/or raw data. Thanks very much.
 

Cataceous

Super Moderator
Thanks for your comments. Take a look at the SD for age on the IM treatment group. There's some really older dudes in that group. Hard to make any conclusions unless we had the paper or raw data. I'm with you, I can't make the numbers for TT in Table 1 vs Table 2A quite work and I'd have to see how they are defining their multivariate regression terms and if they are normalizing their coefficients based on z-scores. Hilarious we are crucifying a poster presentation but this is cool data so we might as well get the conclusions right.
Agreed. I would love to have the raw data to play with. It seems as though the N for the IM group is big enough that you could look at a subset having age characteristics better matching the SC group.
 

readalot

Active Member
Agreed. I would love to have the raw data to play with. It seems as though the N for the IM group is big enough that you could look at a subset having age characteristics better matching the SC group.
Bingo, you could bootstrap both groups and see what you see. Just inside one group (IM or sub-Q), there's some fun analyses you could do.
 

madman

Super Moderator
This is very interesting. Thanks for posting!! What I would like to know is the frequency of injection for each group. The SubQ Test E group was almost certainly once a week because the "autoinjector" Test E group was clearly Xyosted. I do wonder about the more "old-school" IM group. Did they also get the old-school every two weeks IM treatment? Or was it once a week? Doubt that it was more than once a week because the ALL of the 6 or 7 urologists and endocrinologists I've seen can't get past once a week. I often tease them by saying "I know people who dose daily." Anyway.... I'm going to email one of the authors.


I would put money on it that injection frequency was once weekly as it is clearly stated Subcutaneous testosterone enanthate-autoinjectors (SCTE-AI).

There is only one FDA-approved autoinjector on the market and that is Xyosted (testosterone enanthate) which is meant for once-weekly subcutaneous injections.

It comes in three dosage strengths, 50 mg, 75 mg, and 100 mg.

The recommended starting dose is 75 mg/week and many of the studies on Xyosted use the starting dose of 75 mg/week and titrate up or down depending on T level achieved/relief of low-t symptoms or lack thereof.

Would make no sense to use different doses let alone injection frequencies (IM vs sub-Q).

Even then 75 mg/wk (IM/sub-q) was most likely the dose used in the study and would seem reasonable looking at the TT troughs achieved on both protocols.

IM-TC

SCTE-AI


n=188

n=114


mean (SD)

mean (SD)


536.4 (295)

552.5 (207)


.



Aim: The purpose of this study was to confirm the safety and characterize the pharmacokinetic (PK) profile of the subcutaneous TE auto-injector (SCTE-AI) in adult men with TD.

Methods:
In this phase III, 26-week study, 133 men 18-75 years of age with symptomatic TD self-administered SCTE-AI 75 mg once weekly for 6 weeks from July 2015 to June 2016. Dosing was adjusted when indicated to 50 mg or 100 mg to maintain T trough levels between 350 and 650 ng/dL (12.1-22.5 nmol/L). PK data were collected from a subgroup of patients receiving 75 mg SCTE-AI through week 12. Safety, including ambulatory blood pressure monitoring (ABPM), lipid levels, and adverse drug reactions, and PK were assessed.



PK Population Substudy PKs

In the PK substudy population (patients who received 75 mg SCTE-AI through week 12), TT concentrations increased from predose week 1 to week 12 (Figure 3A). Mean TT Ctrough increased from 223.7 ng/dL (7.8 nmol/L) at predose week 1, to 373.7 ng/dL (13.0 nmol/L), 478.9 ng/dL (16.6 nmol/L), and 541.2 ng/dL (18.8 nmol/L) at weeks 1, 6, and 12, respectively. The majority of the 21 PK substudy patients had TT Cavg0-168h 300-1,100 ng/dL (10.4-38.1 nmol/L): 18 patients (86%), 20 patients (95%), and 21 patients (100%) at weeks 1, 6, and 12, respectively. TE, DHT, and E2 concentrations also increased as anticipated from week 1 to week 12, and from predose to postdose at scheduled time points within each of weeks 1, 6, and 12 (Figure 3BeD). DHTE was undetectable at most time points in most patients. Endocrine parameters of follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin decreased from baseline to weeks 13 and 26/ET (Supplemental Table 4).

Screenshot (2686).png
 

bennettjc

Member
Great points. I didn't mention but I was assuming sub-Q group was definitely Xyosted as they (Antares) have been sponsoring a bunch of research in this arena. I was also assuming weekly dosing frequency and same dosage between groups [some of these papers titrate the dose (50, 75 or 100 mg weekly) to target Cavg in range over the course of the study]. But you are correct we don't know the details. If you are going to email the authors I'd be happy to participate in a "peer-review" if they are willing to share more details and/or raw data. Thanks very much.

I did email one of the authors. And he was quite nice. It was easy to track down his email address. I am pretty sure he wouldn't mind if you or anyone else contacted him:
UC Irvine - Faculty Profile System (email included).

He did confirm that the sub-Q group received Xyosted. And the other group was dosed weekly. Also: "the IM group was all 100mg cypionate, the Xyosted was a combination of 75 and 100mg. 75mg Xyosted tends to mirror levels obtained with 100mg IM in general."

Bennett
 

bennettjc

Member
I would put money on it that injection frequency was once weekly as it is clearly stated Subcutaneous testosterone enanthate-autoinjectors (SCTE-AI).

There is only one FDA-approved autoinjector on the market and that is Xyosted (testosterone enanthate) which is meant for once-weekly subcutaneous injections.

It comes in three dosage strengths, 50 mg, 75 mg, and 100 mg.

The recommended starting dose is 75 mg/week and many of the studies on Xyosted use the starting dose of 75 mg/week and titrate up or down depending on T level achieved/relief of low-t symptoms or lack thereof.

Would make no sense to use different doses let alone injection frequencies (IM vs sub-Q).

Even then 75 mg/wk (IM/sub-q) was most likely the dose used in the study and would seem reasonable looking at the TT troughs achieved on both protocols.

IM-TC

SCTE-AI


n=188

n=114


mean (SD)

mean (SD)


536.4 (295)

552.5 (207)


.











Aim: The purpose of this study was to confirm the safety and characterize the pharmacokinetic (PK) profile of the subcutaneous TE auto-injector (SCTE-AI) in adult men with TD.

Methods:
In this phase III, 26-week study, 133 men 18-75 years of age with symptomatic TD self-administered SCTE-AI 75 mg once weekly for 6 weeks from July 2015 to June 2016. Dosing was adjusted when indicated to 50 mg or 100 mg to maintain T trough levels between 350 and 650 ng/dL (12.1-22.5 nmol/L). PK data were collected from a subgroup of patients receiving 75 mg SCTE-AI through week 12. Safety, including ambulatory blood pressure monitoring (ABPM), lipid levels, and adverse drug reactions, and PK were assessed.



PK Population Substudy PKs

In the PK substudy population (patients who received 75 mg SCTE-AI through week 12), TT concentrations increased from predose week 1 to week 12 (Figure 3A). Mean TT Ctrough increased from 223.7 ng/dL (7.8 nmol/L) at predose week 1, to 373.7 ng/dL (13.0 nmol/L), 478.9 ng/dL (16.6 nmol/L), and 541.2 ng/dL (18.8 nmol/L) at weeks 1, 6, and 12, respectively. The majority of the 21 PK substudy patients had TT Cavg0-168h 300-1,100 ng/dL (10.4-38.1 nmol/L): 18 patients (86%), 20 patients (95%), and 21 patients (100%) at weeks 1, 6, and 12, respectively. TE, DHT, and E2 concentrations also increased as anticipated from week 1 to week 12, and from predose to postdose at scheduled time points within each of weeks 1, 6, and 12 (Figure 3BeD). DHTE was undetectable at most time points in most patients. Endocrine parameters of follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin decreased from baseline to weeks 13 and 26/ET (Supplemental Table 4).

View attachment 11767

Madman - Please see what I just wrote to readalot.
Bennett
 

readalot

Active Member

Clarifying comments that could be used to improve subsequent study to validate hypotheses discussed above. Thanks for clarifying with the author @bennettjc on the study details!

I don't think we have enough information about that study to make meaningful conclusions. If I remember correctly, I thought my takeaway was the weekly dose for the control arm of the study was different that the Xyosted-equivalent arm:


bennettjc said:

He did confirm that the sub-Q group received Xyosted. And the other group was dosed weekly. Also: "the IM group was all 100mg cypionate, the Xyosted was a combination of 75 and 100mg. 75mg Xyosted tends to mirror levels obtained with 100mg IM in general."

- Compare 75 mg/week or 100 mg/week (pick a number) of TC dose-equivalent - dosed every day vs once weekly for the win! Test hypothesis that dosing frequency makes a difference (peak vs trough, etc).

- Or compare sub-Q vs IM once per week at XX mg/week.

- But please don't compare Xyosted dosed at 75-100 mg/week vs TC at 100 mg/week, then have two different groups wrt mean age and conclude that Xyosted is the winner. My Hct at 70 mg/week TC very different than at 100 mg/week (same dosing frequency). Some of us very sensitive evidently.
 
Last edited:
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