IM versus Sub-q T Injections: Effect on TT, hematocrit, E2, and PSA

Nelson Vergel · Aug 13, 2021

Principles of Testosterone and hCG Injection Technique - Excel Male Health Forum

Selecting the Devices There are many different syringes and needles, suiting many different procedures. It is important to choose the needles and syringes carefully according to the type of injection to be administered. For example, the length and gauge of the needle and type of syringe must...

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Bubbs · Oct 16, 2021

It's interesting that the TT was so close between the 2 groups

I've tried SubQ a few times in the past as I hate the idea of IM scar tissue, but my TT mg for mg and on the same frequency (3x weekly) has always been significantly lower on SubQ

Nelson Vergel · Dec 29, 2021

TRT with Subcutaneous Testosterone Injections: A Safe, Practical and Reasonable Option - Excel Male Health Forum

Abstract Context: Injections with intramuscular testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also the most inexpensive modality. However, they are difficult to self-administer and associated with some...

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Nelson Vergel · Dec 30, 2021

Subcutaneous Testosterone Injections Are A Good Alternative to Intramuscular Ones - Excel Male Health Forum

Abstract Context: Testosterone (T) is commonly administered intramuscularly to treat hypogonadal males and female-to-male (FTM) transgender patients. However, these injections can involve significant discomfort and may require arrangements for administration by others. Objective: We assessed...

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Charliebizz · Feb 28, 2022

Bubbs said:
It's interesting that the TT was so close between the 2 groups

I've tried SubQ a few times in the past as I hate the idea of IM scar tissue, but my TT mg for mg and on the same frequency (3x weekly) has always been significantly lower on SubQ

Were you testing at the same time ? Maybe that could be the problem ? If sub q takes longer to peak!

madman · Dec 31, 2023

Had been sitting on this paper for a long time and thought I had posted the full paper in this thread already!

Keep in mind this is not true trough (7 days post-injection) as blood was drawn 5-6 days after the last injection.

*Men were either treated with IM-TC alone, SCTE-AI alone, or started with IM-TC and crossed over to SCTE-AI with at least 6 weeks of washout between the 2 treatment modalities. Dosing for IM-TC and SCTE-AI was 100 mg weekly.

*Serum values of TT (280 to 1,100 ng/dL), E2 (10 to 50 pg/mL), HCT (38.8% to 50.0%) and PSA (<2.5 ng/mL) were drawn prior to initiation of TRT and at 12-week followup. Baseline laboratory blood draws were specified to occur in the morning prior to 10:00 a.m. and 5-6 days after their last injection to observe trough TT values.

*After an average follow-up of 14.2 weeks after initiating TRT, both cohorts had significant increases in trough TT compared to their baseline levels (IM-TC:313.6 ng/dL to 536.4 ng/dL, p <0.001; SCTE-AI: 246.6ng/dL to 552.8 ng/dL, p <0.001)

*Post-therapy, the SCTE-AI cohort had significantly lower, HCT and E2, while TT and PSA levels were not significantly different between the treatment arms.

*Limitations to this study include its retrospective nature preventing randomization of patients. We also acknowledge the limitations associated with the portion of participants who had been treated with both TRT modalities, of whom all had received IM-TC prior to switching to SCTE-AI. This was performed due to constraints with our relatively small sample size. A washout period was utilized prior to SCTE-AI initiation, though a more robust study in the future would compare independent patient pools that receive only 1 TRT modality. While testosterone enanthate and testosterone cypionate are both short-acting testosterone esters, our analysis of the SCTE-AI and IM-TC compares 2 different formulations of injectable testosterone. Furthermore, our databases lacked depth in clinical information, such as body mass index, or relevant medication use, such as aromatase inhibitors, which is rarely used in tandem with TRT in our practices. We acknowledge these factors may act as unknown confounders. Lastly, as the SCTE-AI is a newer device, future studies will benefit from larger sample sizes and longer follow-ups as the SCTE-AI becomes more widely used.

Comparison of Outcomes for Hypogonadal Men Treated with Intramuscular Testosterone Cypionate versus Subcutaneous Testosterone Enanthate - PubMed

While IM-TC and SCTE-AI provide a significant increase in TT levels, 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 potentially preferable safety profile...

pubmed.ncbi.nlm.nih.gov

HYPOGONADISM in men is characterized by diminished serum testosterone levels clinically manifesting as depressed libido and sexual dysfunction in addition to fatigue, decreased muscle mass, poor bone mineralization, increased body fat, gynecomastia, and hot flashes.1,2

Hypogonadism also has complex associations with chronic conditions such as type 2 diabetes mellitus, obesity, and metabolic syndrome that require a multifaceted approach to therapy including behavioral changes as well as pharmacological interventions.3,4

The estimated incidence of hypogonadism in the United States is approximately 481,000 cases per year.5 However, this rate will likely rise due to the increasing proportion of aging males as well as the worsening prevalence of metabolic disorders.6,

While intramuscular (IM) testosterone injections are a conventional method for testosterone replacement therapy (TRT), patient compliance to treatment can be deterred by pain associated with the large needle bore required as well as some of the problematic associated side effects.8 Injectable testosterone is esterified to decrease polarity, increase solubility in oils, slow release into the bloodstream, and increase half-life.9 Testosterone cypionate and testosterone enanthate are the most common esters for TRT with studies demonstrating that both formulations have similar pharmacokinetic profiles.9-11 A novel subcutaneous testosterone enanthate autoinjector (SCTEAI) gained approval by the U.S. Food and Drug Administration for clinical use and is available as a self-administered, once-weekly dose with a small 5/8 inch 27-gauge needle.12,13 The SCTE-AI has been shown to safely elevate testosterone levels to eugonadal ranges and offers a reduced peak-to-trough ratio compared to IM testosterone, resulting in a more steady state of available testosterone within normal physiological ranges.8,12,14 This is especially important to consider as supraphysiological levels of testosterone have been associated with an undesirable rise in estradiol (E2), hematocrit (HCT), and prostate-specific antigen (PSA).15-17 In this study, we aim to compare the novel SCTE-AI to IM testosterone cypionate (IM-TC) in their ability to effectively increase total testosterone (TT) levels as well as evaluating safety profiles by measuring E2, HCT, and PSA responses.

METHODS

Institutional review board approval was obtained, and data collection and storage were performed in a de-identified fashion in compliance with the Health Insurance Portability and Accountability Act (IRB No. 2017-3746). This was a retrospective study on prospectively managed databases between 2 high-volume practices. Between October 2016 and October 2019, 234 hypogonadal men were treated with injectable forms of TRT. Men with a history of prostate cancer were excluded from this study. Men were either treated with IM-TC alone, SCTE-AI alone or started with IM-TC and crossed over to SCTE-AI with at least 6 weeks of washout between the 2 treatment modalities. Dosing for IM-TC and SCTE-AI was 100 mg weekly. Serum values of TT (280 to 1,100 ng/dL), E2 (10 to 50 pg/mL), HCT (38.8% to 50.0%) and PSA (<2.5 ng/mL) were drawn prior to initiation of TRT and at 12-week followup. Baseline laboratory blood draws were specified to occur in the morning prior to 10:00 a.m. and 5-6 days after their last injection to observe trough TT values. If HCT levels rose beyond a threshold of 54%, TRT was immediately discontinued and therapeutic phlebotomy was ordered. TRT was also terminated if E2 levels were elevated 50 pg/mL. TRT was finally discontinued when the PSA increased by more than 0.75 ng/mL or surpassed 4 ng/mL, which also prompted a prostate cancer evaluation.

Statistical analyses were performed on the IBM SPSS Statistics program (IBM, Armonk, New York). Pre and posttherapy levels of TT, E2, HCT, and PSA were natural-log-transformed to improve normality in distributions. Paired t-tests determined whether pre and post-therapy levels were significantly different within cohorts and independent sample t-tests determined whether baseline and post-therapy levels were different between the cohorts. Four linear regression models were created to assess whether TRT modality was an independent predictor of post-therapy TT, E2, HCT, or PSA. Fisher’s exact tests compared the incidence of significantly elevated levels of post-therapy E2 and HCT, which were defined as 50 pg/mL and 54%, respectively. Significant adverse events, such as major adverse cardiac events, as well as aberrant elevations in E2, HCT, and PSA were carefully monitored.

RESULTS

A total of 234 hypogonadal men were treated withTRT of whom 124 were treated with IM-TC alone,46 were treated with SCTE-AI alone, and 64 were treated with both modalities. Overall, the mean age of every participant in this study was 54.2 years (SD: 12.7). The 188 men who received IM-TC had a mean age of 54.4 years (SD: 13.4), and the 110 who received SCTE-AI had a mean age of 49.7 years (SD: 10.5; table 1). The IM-TC cohort had significantly higher levels of baseline TT (313.6 ng/dL vs 246.6 ng/dL,p[0.004) and E2 (30.4 pg/mL vs 25.5 pg/mL,p[0.005) whereas the 2 cohorts had similar pretherapy levels of HCT (45.2% vs 44.7%, p[0.365) and PSA (1.41 ng/dL vs 1.07 ng/dL, p[0.070). These baseline differences remained statistically significant after natural-log transformation (table 1). Of note, not all secondary lab values were available at the time of analysis as they were drawn significantly beyond the 12-week follow-up period. Among the IM TC group, there were 100 men with E2 levels, 114 with HCT, and 99 with PSA values. In the SCTE-AI group, 106 had E2 levels, 107 had HCT, and 105 had PSA values for analysis.

After an average follow-up of 14.2 weeks after initiating TRT, both cohorts had significant increases in trough TT compared to their respective baseline levels (IM-TC: 313.6 ng/dL to 536.4 ng/dL, p <0.001; SCTE-AI: 246.6 ng/dL to 552.8 ng/dL, p <0.001). Both cohorts also experienced post-therapy rises in E2 (IM-TC: 30.4 pg/mL to 46.6 pg/mL, p <0.001; SCTE-AI: 25.5 pg/mL to 33.1 pg/mL, p <0.001) and HCT (IM-TC: 45.2% to 48.4%, p <0.001; SCTE-AI: 44.7% to 46.2%, p <0.001). Post-therapy PSA levels were equivalent to baseline for both the IM-TC (1.41 ng/dL to 1.26 ng/dL, p[0.179) and SCTE-AI cohorts (1.07 ng/dL to 1.17 ng/dL, p[0.390). The IM-T Ccohort had a significantly greater proportion of men with post-therapy E2 elevations of 50 pg/mL with 31 (31%) men in this group passing the threshold compared to only 11 (10.4%) men in the SCTE-AI group (p <0.001). The IM-TC cohort also had a greater proportion of patients experiencing polycythemia with 12 (10.5%) in the IM-TC group compared to only 1 (0.9%) participant in the SCTE-AI group with post-therapy HCT 54% (p[0.003).

After adjusting for age, baseline TT, and baseline E2, the type of TRT received was not significantly associated with post-therapy TT levels (B: 0.109, SE: 0.057, p[0.057; Table 2). Age (p <0.001) and baseline E2 (p[0.024) were significantly associated with higher levels of post-therapy TT (Table 2).SCTE-AI was found to be independently associated with lower post-therapy E2 (B: 0.235, SE: 0.068,p <0.001) and HCT (B: 0.072, SE: 0.012, p <0.001; Tables 3 and 4). Baseline E2 (B: 0.274, SE: 0.092,p[0.004) was significantly associated with posttherapy E2 (Table 3). While age was a significant predictor of post-therapy PSA (B: 0.013, SE: 0.005,p[0.005), the type of TRT modality was not significantly associated with post-therapy elevation of PSA (B: 0.004, SE: 0.102, p[0.965; Table 5). In the SCTE-AI group, 1 patient saw an aberrant rise in PSA and was diagnosed with prostate cancer. TRT was immediately terminated. No significant adverse events, including major adverse cardiac events, were reported.

DISCUSSION

This is the first investigation comparing the novel SCTE-AI to IM testosterone for the treatment of hypogonadism in men. At a mean follow-up of 14.2 weeks, both TRT modalities significantly improved trough TT levels to eugonadal ranges. While both modalities appropriately raise TT, IM testosterone is known to produce wide fluctuations that have been linked to variability in libido, mood, and energy.18,19 Investigations into subcutaneous administration, on the other hand, have achieved therapeutic levels of testosterone without such variability.8,18 Manual subcutaneous injections should theoretically provide similar benefits to the SCTE-AI, though this would require thorough patient training and/or repeated clinic visits for drug administration which would likely negatively impact patient compliance as it does for IM testosterone. The autoinjector mechanism also decreases anxiety for men with needle phobia.

While both cohorts in our study experienced rises in E2 after TRT, men treated with SCTE-AI had significantly lower post-therapy E2 levels, approximately 20% less compared to the IM-TC cohort (B: 0.235, SE: 0.068, p <0.001; table 3). We found that those treated with IM-TC experienced elevated E2 50 pg/mL more often with 31% surpassing this threshold compared to only 10% in the SCTE-AI cohort (p = 0.003). Prior investigations have shown that short-acting IM testosterone may induce higher levels of E2 compared to other TRT modalities, including transdermal gels and pellets.15,17 This may be due to supraphysiological peaks of testosterone, which drastically increases bioavailable testosterone for aromatization into E2.17,20 While uncommon, clinical manifestations of hyperestrogenism, such as gynecomastia, have been reported in men treated with TRT.21 No one in this study experienced such symptoms. If a patient develops supraphysiological estrogen levels, aromatase inhibitors can be utilized, though this is considered an off-label use.22

Major guidelines define erythrocytosis to be 54% HCT and require interruption of TRT and/or therapeutic phlebotomy.1,23 While HCT significantly rose for both TRT modalities, only 1% in the SCTE-AI group reached the 54% threshold compared to the 10.5% in the IM-TC cohort (p <0.001). Men who received SCTE-AI experienced 7% lower post-therapy HCT levels compared to those treated with IM-TC (B: 0.072, SE: 0.012, p <0.001; Table 4). Erythrocytosis has been associated with supraphysiological peaks of testosterone and E2, phenomena anticipated with short-acting IM testosterone.24,25 One study found that IM testosterone significantly elevated HCT higher than transdermal gel or pellets. 15 15 Furthermore, short-acting IM testosterone has been reported to induce erythrocytosis in up to 40% of patients who receive this form of TRT.24 While brief episodes of mild erythrocytosis secondary to TRT have not been linked to thromboembolic events, HCT should be closely monitored to minimize this potential risk.2,24

Neither group in this study experienced significant rises in PSA after TRT, which is consistent with other prospective studies (table 5).17,24,26 While elevation in PSA can be expected after TRT initiation, these increases have not been shown to be related to a greater risk of developing prostate cancer.24,27,28 The 2018 American Urological Association guidelines on testosterone deficiency report a lack of evidence in the link between TRT and risk for prostate cancer.2 Modern understanding of testosterone and prostate cancer has greatly advanced since the introduction of the “saturation model” by Rhoden and Morgentaler, which sought to explain the lack of increased prostate cancer risk in men receiving TRT.24 One such study was an analysis of the National Prostate Cancer Register of Sweden database, which did not find an association between TRT and prostate cancer risk.29 The majority of studies on this topic have been either retrospective, population analyses, or prospective with small sample sizes. Currently, the Study to Evaluate the Effect of Testosterone Replacement Therapy on the Incidence of Major Adverse Cardiovascular Events and Efficacy Measures in Hypogonadal Men (TRAVERSE) is ongoing and is designed as a prospective analysis of how TRT affects multiple safety concerns including prostate cancer risk.30

This is the first study of the novel SCTE-AI indirect comparison to another TRT modality for the treatment of hypogonadism in men. Limitations to this study include its retrospective nature preventing randomization of patients. We also acknowledge the limitations associated with the portion of participants who had been treated with both TRT modalities, of whom all had received IM-TC prior to switching to SCTE-AI. This was performed due to constraints with our relatively small sample size. A washout period was utilized prior to SCTE-AI initiation, though a more robust study in the future would compare independent patient pools that receive only 1 TRT modality. While testosterone enanthate and testosterone cypionate are both short-acting testosterone esters, our analysis of the SCTE-AI and IM-TC compares 2 different formulations of injectable testosterone. Furthermore, our databases lacked depth in clinical information, such as body mass index, or relevant medication use, such as aromatase inhibitors, which is rarely used in tandem with TRT in our practices. We acknowledge these factors may act as unknown confounders. Lastly, as the SCTE-AI is a newer device, future studies will benefit from larger sample sizes and longer follow-ups as the SCTE-AI becomes more widely used.

CONCLUSION

This is the first study to compare the SCTE-AI to another form of TRT. While IM-TC and SCTE-AI both provided significant increases in TT levels, the SCTE-AI was associated with lower levels of E2 and HCT compared to IM-TC after adjusting for baseline differences in the cohorts. With its improved peak-to-trough ratio that reduces physiological testosterone exposure, the SCTE-AI has been shown to be an effective testosterone delivery system with a potentially preferable safety profile over short-acting IM testosterone.

FunkOdyssey · Jan 1, 2024

New Study - SubQ Alledgedly Leads To Lower HCT/E2/PSA Than IM Just Published

Readalot sent me a link to this thread where bennettjc posted the full text of the paper back in April 2022. He says you must be slipping @madman , and also, happy new year. lol

	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

IM versus Sub-q T Injections: Effect on TT, hematocrit, E2, and PSA

How to Inject Testosterone Intramuscularly, Shallow IM or Subcutaneously ? - Excel Male Health Forum

Nelson Vergel

Principles of Testosterone and hCG Injection Technique - Excel Male Health Forum

Bubbs

Nelson Vergel

TRT with Subcutaneous Testosterone Injections: A Safe, Practical and Reasonable Option - Excel Male Health Forum

Nelson Vergel

Subcutaneous Testosterone Injections Are A Good Alternative to Intramuscular Ones - Excel Male Health Forum

Charliebizz

madman

Comparison of Outcomes for Hypogonadal Men Treated with Intramuscular Testosterone Cypionate versus Subcutaneous Testosterone Enanthate - PubMed

FunkOdyssey

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