madman
Super Moderator
* SubQ injectable TRT is a relatively novel therapy aimed at minimizing the drawbacks associated with IM TRT while potentially offering steadier absorption.
* This IRB-approved study (22111501) investigated our institution’s use of non-proprietary SubQ TRT with testosterone cypionate (T CYP), for the treatment of hypogonadism in men. T CYP was administered using a standard 27- gauge 1 / 2-in. insulin needle and 1 mL syringe to deliver 100 mg or 0.5 mL
Male hypogonadism, defined as a total testosterone (TT) level < 300 ng/dL in combination with at least one clinical symptom, affects millions of men in the United States. Treatment of hypogonadism involves testosterone replacement therapy (TRT) with the goal of symptom reduction, maintenance of virilization, and prevention of osteoporosis and sarcopenia.1
Currently available TRT formulations include topical gels, transdermal patches, buccal patches, subcutaneous (SubQ) implantable pellets, nasal sprays, oral tablets, and intramuscular (IM) or SubQ injectables. SubQ injectable TRT is a relatively novel therapy aimed at minimizing the drawbacks associated with IM TRT while potentially offering steadier absorption. Classic IM T injections are associated with pain, often require office visits for proper administration, and can result in troughs and peaks due to its dosing schedule.2 Given evidence surrounding the safety, efficacy, and tolerability of SubQ TRT, it appears to be a reasonable option for patients undergoing treatment.2 Xyosted (testosterone enanthate) is the only commercially available FDA-approved SubQ TRT, which can be financially restrictive to some patients.
This IRB-approved study (22111501) investigated our institution’s use of non-proprietary SubQ TRT with testosterone cypionate (T CYP), for the treatment of hypogonadism in men. T CYP was administered using a standard 27- gauge 1 / 2-in. insulin needle and 1 mL syringe to deliver 100 mg or 0.5 mL. Patients (n = 93) were included if they met the diagnosis of hypogonadism. They were accrued in 2020 and 2021. Patients were informed of the off-label use of non-proprietary SubQ TRT. Patients with baseline TT > 300 ng/dL were included if they had a previous diagnosis of hypogonadism and were transitioned to SubQ TRT from an alternative TRT. A non-validated satisfaction survey was conducted via email or phone and consisted of five questions about pain with, satisfaction with, and ease of use of SubQ TRT as well as preference over previous forms of TRT if applicable.
Most patients (n = 82) were on a weekly injection schedule, nine patients were on a twice weekly schedule, and two patients were on an every-other-week schedule. Baseline TT for the entire group was 333.0 (258.0) and increased to 569.5 (441.6) at the last follow-up visit (P < .01). Patients who had not received any previous TRT saw an increase in TT by 182.9 ng/dL (P < .01) (from 208.45 to 391.32 ng/dL at latest follow-up). Baseline prostate specific antigen (PSA) was 1.5 (1.8) and baseline hematocrit (Hct) was 46.5% (5.1%), with no statistically significant changes to either noted at any follow-up time point.
Patient satisfaction was assessed over the phone or through an email questionnaire (n = 57, 61%). On a scale from 0 (low) to 5 (high), mean satisfaction with SubQ TRT was 4.2 (0.9) and 3.2 (1.1) with previous forms of TRT. Patients found SubQ TRT to be both easier (25/35, 71%) and less painful (28/35, 80%). Only 29% of patients (11/38) said they would return to their previous TRT after initiation of SubQ TRT.
These data provide early evidence of the utility of non-proprietary T CYP delivered subcutaneously for the treatment of male hypogonadism, which is effective at increasing serum testosterone levels to a therapeutic range. Overall patient satisfaction with this TRT delivery method was high. The average length of follow-up was 17.9 (14.3) months. Over the course of the study, mean hematocrit and PSA rose (by 1.74 and 0.39, respectively), however the increased levels were not statistically significant.
Current literature indicates that increases in hematocrit are a well-documented effect of TRT, whereas PSA levels remain largely unchanged in most patients. The American Urologic Association (AUA) guidelines acknowledge the growing body of evidence against a link between TRT and prostate cancer.3
In our study, erythrocytosis secondary to TRT was defined as Hct > 54%. AUA guidelines indicate that there is no clear risk of major adverse cardiac events (MACE) associated with TRT, and that untreated low testosterone levels are associated with MACE.3 Recent data from the TRAVERSE trial indicate that, among patients at high cardiovascular risk, TRT gel was noninferior to placebo with respect to MACE.4
We did not observe a rise in Hct > 54% in any patient with a baseline Hct < 54%, including 20 men with baseline Hct > 50% who switched to SubQ TRT from another form of TRT, suggesting that SubQ TRT may carry a lower risk of inducing erythrocytosis. This is yet to be determined and would require larger, randomized, and longer-term prospective data to be proven.
We utilized the Sexual Healthy Inventory for Men (SHIM) questionnaire as a metric for erectile dysfunction (ED). SHIM scores numerically rose over the course of the study. Mean baseline SHIM score was 12.36 (8.5) and rose to 18.75 (4.8), but the rises were not statistically significant (P= .07). Current literature on the impact of TRT on erectile function tends to support a positive correlation between TRT and improvement in ED.3 Because SubQ TRT is relatively new, its role in improving ED compared with other administration modalities remains to be determined, though it is likely similar.
We believe this study provides evidence that SubQ TRT with T CYP is an effective alternative TRT formulation; however, our research has limitations. Several conclusions were constrained by the retrospective design of this study as well as the lack of a defined follow-up timeline. A relatively high percentage (39%) of patients did not complete the survey. Furthermore, a standardized validated assessment of a clinical response to SubQ TRT would strengthen the external validity of this study.
While patient success with this novel therapy provides anecdotal support for its noninferiority compared with alternative TRT approaches, patients included in our study fell on a spectrum of previous TRT experience, from treatment naïve to prior multi-modal therapy. Baseline TT was >300 ng/dL largely because of the large number of patients in this study who were on a different form of TRT with immediate transitioning to SubQ TRT. No TRT-naïve patients in this cohort had a baseline T > 300 ng/dL; the mean baseline TT in TRT naive patients was 208.4 (54.8), well within guideline recommendations for therapy initiation.
Several patients (n = 14) discontinued SubQ TRT for reasons including cost (n = 1), pharmacy access issues (n = 1), patient-reported complications such as scar tissue (n = 1) and bruising (n = 1), residual hypogonadal symptoms despite normal TT values or preference for alternative therapies (n = 7), and difficulty preparing or administering the medication (n = 1). This cohort included one patient who was diagnosed with grade group 1 prostate cancer (<1% total tissue) after a transurethral resection of the prostate. One patient suffered a stroke, though his hematocrit never rose above 54%. In addition, comorbidities in this patient, including hypertension, coronary artery disease, and obstructive sleep apnea, make the association between SubQ TRT and cerebrovascular disease less clear.
Nonetheless, exploring the potential issues with SubQ TRT is important for understanding its utility as an alternative to other, more established therapies.
* This IRB-approved study (22111501) investigated our institution’s use of non-proprietary SubQ TRT with testosterone cypionate (T CYP), for the treatment of hypogonadism in men. T CYP was administered using a standard 27- gauge 1 / 2-in. insulin needle and 1 mL syringe to deliver 100 mg or 0.5 mL
Male hypogonadism, defined as a total testosterone (TT) level < 300 ng/dL in combination with at least one clinical symptom, affects millions of men in the United States. Treatment of hypogonadism involves testosterone replacement therapy (TRT) with the goal of symptom reduction, maintenance of virilization, and prevention of osteoporosis and sarcopenia.1
Currently available TRT formulations include topical gels, transdermal patches, buccal patches, subcutaneous (SubQ) implantable pellets, nasal sprays, oral tablets, and intramuscular (IM) or SubQ injectables. SubQ injectable TRT is a relatively novel therapy aimed at minimizing the drawbacks associated with IM TRT while potentially offering steadier absorption. Classic IM T injections are associated with pain, often require office visits for proper administration, and can result in troughs and peaks due to its dosing schedule.2 Given evidence surrounding the safety, efficacy, and tolerability of SubQ TRT, it appears to be a reasonable option for patients undergoing treatment.2 Xyosted (testosterone enanthate) is the only commercially available FDA-approved SubQ TRT, which can be financially restrictive to some patients.
This IRB-approved study (22111501) investigated our institution’s use of non-proprietary SubQ TRT with testosterone cypionate (T CYP), for the treatment of hypogonadism in men. T CYP was administered using a standard 27- gauge 1 / 2-in. insulin needle and 1 mL syringe to deliver 100 mg or 0.5 mL. Patients (n = 93) were included if they met the diagnosis of hypogonadism. They were accrued in 2020 and 2021. Patients were informed of the off-label use of non-proprietary SubQ TRT. Patients with baseline TT > 300 ng/dL were included if they had a previous diagnosis of hypogonadism and were transitioned to SubQ TRT from an alternative TRT. A non-validated satisfaction survey was conducted via email or phone and consisted of five questions about pain with, satisfaction with, and ease of use of SubQ TRT as well as preference over previous forms of TRT if applicable.
Most patients (n = 82) were on a weekly injection schedule, nine patients were on a twice weekly schedule, and two patients were on an every-other-week schedule. Baseline TT for the entire group was 333.0 (258.0) and increased to 569.5 (441.6) at the last follow-up visit (P < .01). Patients who had not received any previous TRT saw an increase in TT by 182.9 ng/dL (P < .01) (from 208.45 to 391.32 ng/dL at latest follow-up). Baseline prostate specific antigen (PSA) was 1.5 (1.8) and baseline hematocrit (Hct) was 46.5% (5.1%), with no statistically significant changes to either noted at any follow-up time point.
Patient satisfaction was assessed over the phone or through an email questionnaire (n = 57, 61%). On a scale from 0 (low) to 5 (high), mean satisfaction with SubQ TRT was 4.2 (0.9) and 3.2 (1.1) with previous forms of TRT. Patients found SubQ TRT to be both easier (25/35, 71%) and less painful (28/35, 80%). Only 29% of patients (11/38) said they would return to their previous TRT after initiation of SubQ TRT.
These data provide early evidence of the utility of non-proprietary T CYP delivered subcutaneously for the treatment of male hypogonadism, which is effective at increasing serum testosterone levels to a therapeutic range. Overall patient satisfaction with this TRT delivery method was high. The average length of follow-up was 17.9 (14.3) months. Over the course of the study, mean hematocrit and PSA rose (by 1.74 and 0.39, respectively), however the increased levels were not statistically significant.
Current literature indicates that increases in hematocrit are a well-documented effect of TRT, whereas PSA levels remain largely unchanged in most patients. The American Urologic Association (AUA) guidelines acknowledge the growing body of evidence against a link between TRT and prostate cancer.3
In our study, erythrocytosis secondary to TRT was defined as Hct > 54%. AUA guidelines indicate that there is no clear risk of major adverse cardiac events (MACE) associated with TRT, and that untreated low testosterone levels are associated with MACE.3 Recent data from the TRAVERSE trial indicate that, among patients at high cardiovascular risk, TRT gel was noninferior to placebo with respect to MACE.4
We did not observe a rise in Hct > 54% in any patient with a baseline Hct < 54%, including 20 men with baseline Hct > 50% who switched to SubQ TRT from another form of TRT, suggesting that SubQ TRT may carry a lower risk of inducing erythrocytosis. This is yet to be determined and would require larger, randomized, and longer-term prospective data to be proven.
We utilized the Sexual Healthy Inventory for Men (SHIM) questionnaire as a metric for erectile dysfunction (ED). SHIM scores numerically rose over the course of the study. Mean baseline SHIM score was 12.36 (8.5) and rose to 18.75 (4.8), but the rises were not statistically significant (P= .07). Current literature on the impact of TRT on erectile function tends to support a positive correlation between TRT and improvement in ED.3 Because SubQ TRT is relatively new, its role in improving ED compared with other administration modalities remains to be determined, though it is likely similar.
We believe this study provides evidence that SubQ TRT with T CYP is an effective alternative TRT formulation; however, our research has limitations. Several conclusions were constrained by the retrospective design of this study as well as the lack of a defined follow-up timeline. A relatively high percentage (39%) of patients did not complete the survey. Furthermore, a standardized validated assessment of a clinical response to SubQ TRT would strengthen the external validity of this study.
While patient success with this novel therapy provides anecdotal support for its noninferiority compared with alternative TRT approaches, patients included in our study fell on a spectrum of previous TRT experience, from treatment naïve to prior multi-modal therapy. Baseline TT was >300 ng/dL largely because of the large number of patients in this study who were on a different form of TRT with immediate transitioning to SubQ TRT. No TRT-naïve patients in this cohort had a baseline T > 300 ng/dL; the mean baseline TT in TRT naive patients was 208.4 (54.8), well within guideline recommendations for therapy initiation.
Several patients (n = 14) discontinued SubQ TRT for reasons including cost (n = 1), pharmacy access issues (n = 1), patient-reported complications such as scar tissue (n = 1) and bruising (n = 1), residual hypogonadal symptoms despite normal TT values or preference for alternative therapies (n = 7), and difficulty preparing or administering the medication (n = 1). This cohort included one patient who was diagnosed with grade group 1 prostate cancer (<1% total tissue) after a transurethral resection of the prostate. One patient suffered a stroke, though his hematocrit never rose above 54%. In addition, comorbidities in this patient, including hypertension, coronary artery disease, and obstructive sleep apnea, make the association between SubQ TRT and cerebrovascular disease less clear.
Nonetheless, exploring the potential issues with SubQ TRT is important for understanding its utility as an alternative to other, more established therapies.
