madman
Super Moderator
Comparison of Intratesticular Testosterone between Men Receiving Nasal, Intramuscular, and Subcutaneous Pellet Testosterone Therapy: Evaluation of Data from Two Single-Center Randomized Clinical Trials (2023)
Parris Diaz, Rohit Reddy, Ruben Blachman-Braun, Isaac Zucker, Alexandra Dullea, Daniel C. Gonzalez, Eliyahu Kresch, Ranjith Ramasamy
Purpose
Testosterone replacement therapy (TRT) can potentially cause decreased spermatogenesis and subsequent infertility. Recent studies have suggested that 17-hydroxyprogesterone (17-OHP) is a reliable surrogate for intratesticular testosterone (ITT) which is essential for spermatogenesis. We evaluated data from two ongoing open-label, randomized, two-arm clinical trials amongst different treatment preparations (Trial I) subcutaneous testosterone pellets (TP) and (Trial II) intranasal testosterone (NT) or intramuscular testosterone cypionate (TC).
Materials and Methods
Seventy-five symptomatic hypogonadal men (2 serum testosterone <300 ng/dL) were randomized into open-label randomized clinical trials. Eligible subjects received 800 mg TP, 11 mg TID NT or 200 mg ×2 weeks TC. 17-OHP and Serum testosterone were evaluated at baseline and follow-up. The primary outcome was change in 17-OHP. The secondary outcome was change in serum testosterone. Data were analyzed by two-sample and single-sample t-tests, and the determination of equal or unequal variances was computed using F-tests.
Results
Median participant age was 45 years old, with an overall baseline 17-OHP of 46 and serum testosterone of 223.5 ng/dL. 17-OHP significantly decreased in subjects prescribed long-acting TP or TC. The 4-month change in 17-OHP in the NT group (-33.3% from baseline) was less than the change seen in TC (-65.3% from baseline) or TP (-44% from baseline) (p=0.005). All testosterone formulations increased serum testosterone levels at follow-up, with the largest increase seen in TC (+157.6%), followed by NT (+114.3%) and TP (+79.6%) (p=0.005).
Conclusions
Short-acting nasal testosterone appears to have no impact on serum 17-OHP, especially in comparison to long-acting testosterone formulations. All modalities saw significant increases in serum testosterone levels at follow-up. NT and other short-acting testosterone formulations may better preserve ITT and be beneficial for hypogonadal men seeking to maintain fertility potential while on TRT.
INTRODUCTION
Hypogonadism in men presents as a clinical syndrome of low serum testosterone and decreased spermatogenesis combined with symptoms of erectile dysfunction, suppressed mood, and decreased libido [1,2]. Current mainstay treatment exists as testosterone replacement therapy (TRT) in the form of testosterone pellets, intramuscular injections, and nasal testosterone gel. Classic adverse effects of TRT are secondary erythrocytosis, increases in estrogen, and suppression of the hypothalamic-pituitary-gonadal axis impacting fertility [3]
As of 2006, it was reported over 4 million men are impacted by hypogonadism in the United States [4]. Travison et al [5] first described hypogonadism can occur in younger men [6]. In fact, the average age of fathers has been consistently increasing since 1972. Specifically, fathers’ average ages have increased by 4.4 years over the past 45 years [7,8]. The combination of younger men being prescribed TRT and the average age of fathers increasing raises the importance of fertility preservation in men of reproductive age.
Intratesticular testosterone (ITT) is regarded as a critical component for spermatogenesis [9]. Unfortunately, ITT is decreased in men who receive TRT leading to impaired fertility potential. In recent years, 17-hydroxyprogesterone (17-OHP), an intermediate product of steroid metabolism, has been proposed as a surrogate biomarker for ITT and in turn, male fertility (Fig. 1) [7,10,11]. Existing evidence shows strong evidence of an inverse relationship between exogeneous TRT and serum 17-OHP along with an association between favorable semen parameters and increased 17-OHP serum levels [12]. As different TRT formulations have emerged in the market with each its own unique regimen schedule, it is unclear how each therapy impacts ITT. This study presents the first report of two open-label randomized control trials consisting of patients receiving either subcutaneous testosterone pellets (TP), intramuscular (IM), or intranasal testosterone (NT). We were able to quantify the differences each TRT formulation has on ITT using 17-OHP as a biomarker. We hypothesized that long-acting T formulations would decrease ITT compared to short-acting formulations due to short-acting T more closely mimicking the pulsatile secretion of gonadotropin-releasing hormone (GnRH).
Discussion
Usage of long-acting TRT in hypogonadal men was associated with a significantly decreased 17-OHP at follow-up. However, in line with the hypothesis, short-acting NT had the smallest change in 17-OHP following treatment compared to long-acting injectables or pellets. Our study is the first to simultaneously compare the impact of intranasal, intramuscular, and subcutaneous testosterone treatment on endogenous testosterone in hypogonadal males. The results of this study might suggest that short-acting formulations may have less of an impact on the local testicular environment
A plausible explanation for this finding is dosing schedule paired with the short half-life of NT more closely mimics normal physiology allowing for the maintenance of GnRH pulsatility (LH) and its downstream products luteinizing hormone and follicle-stimulating hormone (FSH) [13]. LH then stimulates Leydig cells within the testis to create endogenous testosterone that contributes to subsequent spermatogenesis. Given the increase of serum testosterone and maintenance of ITT, the result of this study should be considered when discussing the optimal TRT regimen for hypogonadal men who are concerned about testis atrophy and future fertility potential.
Long-acting testosterone has been shown to diminish endogenous testosterone production via suppression of the hypothalamic–pituitary–adrenal axis [14]. Men with low endogenous testosterone often suffer from decreased testes volume, and decreased sperm concentration with evidence of increased risk of all-cause and CVD death [15,16]. With an incidence of hypogonadism in 3% to 8% of 20 to 45-year-old men [9], and an average age of first-time fathers 31 years old [17] many hypogonadal males may be unwilling to begin treatment due to contraceptive effects from TRT. To date, physicians have countered this decrease in ITT by prescribing the LH-agonist human chorionic gonadotropin (HCG) to stimulate the testes to produce testosterone, and existing evidence shows sperm count recovery after TRT to 90% within 12 months [18]. However, the cost, lack of insurance coverage, and heavy restrictions imposed by the U.S. Food and Drug Administration (FDA) make HCG inaccessible for many. This study contributes to a clearer understanding of short-acting testosterone formulation's ability to maintain endogenous testosterone and supports previous research suggesting that intranasal testosterone gel can treat hypogonadism while maintaining semen parameters. There is a lack of information on whether hypogonadal men can recover endogenous testosterone production following TRT, and further studies should be done to evaluate this among the various delivery methods.
This study is not without limitations. While 17-OHP is helpful as a surrogate for ITT, it is an imperfect marker as approximately 30% is made by the adrenal glands. Future projects should be sure to include the collection of serum LH and FSH in subjects to better elucidate the pulsatility of GnRH between the various testosterone delivery methods. Given the retrospective study design, we are unable to quantify missed doses, medication non-adherence, nor the proficiency of the clinicians in counseling patients on TRT. In addition, while subjects were instructed regarding the timing of laboratory bloodwork their personal schedules or testing center availability may have precluded optimal profiling. Finally, our data only includes hypogonadal men recruited and treated at a single hospital system and may not be applicable to patients in different settings with replacement regimens beyond FDA recommendations [19-21]. Nevertheless, our study is the first to compare the impact of nasal, intramuscular, and subcutaneous testosterone treatment on 17-OHP in humans using randomized clinical trial data.
CONCLUSIONS
Short-acting nasal testosterone appears to have no impact on serum 17-OHP, especially in comparison to long-acting testosterone formulations. However, all TRT modalities demonstrated significant increases in serum testosterone levels of hypogonadal men at follow-up. Maintenance of 17-OHP gives insight into the testicular micro-environment which is especially important in spermatogenesis and overall male fertility. Intranasal T and other short-acting testosterone formulations may better to preserve ITT and be beneficial for hypogonadal men seeking to maintain fertility potential while on TRT.
Parris Diaz, Rohit Reddy, Ruben Blachman-Braun, Isaac Zucker, Alexandra Dullea, Daniel C. Gonzalez, Eliyahu Kresch, Ranjith Ramasamy
Purpose
Testosterone replacement therapy (TRT) can potentially cause decreased spermatogenesis and subsequent infertility. Recent studies have suggested that 17-hydroxyprogesterone (17-OHP) is a reliable surrogate for intratesticular testosterone (ITT) which is essential for spermatogenesis. We evaluated data from two ongoing open-label, randomized, two-arm clinical trials amongst different treatment preparations (Trial I) subcutaneous testosterone pellets (TP) and (Trial II) intranasal testosterone (NT) or intramuscular testosterone cypionate (TC).
Materials and Methods
Seventy-five symptomatic hypogonadal men (2 serum testosterone <300 ng/dL) were randomized into open-label randomized clinical trials. Eligible subjects received 800 mg TP, 11 mg TID NT or 200 mg ×2 weeks TC. 17-OHP and Serum testosterone were evaluated at baseline and follow-up. The primary outcome was change in 17-OHP. The secondary outcome was change in serum testosterone. Data were analyzed by two-sample and single-sample t-tests, and the determination of equal or unequal variances was computed using F-tests.
Results
Median participant age was 45 years old, with an overall baseline 17-OHP of 46 and serum testosterone of 223.5 ng/dL. 17-OHP significantly decreased in subjects prescribed long-acting TP or TC. The 4-month change in 17-OHP in the NT group (-33.3% from baseline) was less than the change seen in TC (-65.3% from baseline) or TP (-44% from baseline) (p=0.005). All testosterone formulations increased serum testosterone levels at follow-up, with the largest increase seen in TC (+157.6%), followed by NT (+114.3%) and TP (+79.6%) (p=0.005).
Conclusions
Short-acting nasal testosterone appears to have no impact on serum 17-OHP, especially in comparison to long-acting testosterone formulations. All modalities saw significant increases in serum testosterone levels at follow-up. NT and other short-acting testosterone formulations may better preserve ITT and be beneficial for hypogonadal men seeking to maintain fertility potential while on TRT.
INTRODUCTION
Hypogonadism in men presents as a clinical syndrome of low serum testosterone and decreased spermatogenesis combined with symptoms of erectile dysfunction, suppressed mood, and decreased libido [1,2]. Current mainstay treatment exists as testosterone replacement therapy (TRT) in the form of testosterone pellets, intramuscular injections, and nasal testosterone gel. Classic adverse effects of TRT are secondary erythrocytosis, increases in estrogen, and suppression of the hypothalamic-pituitary-gonadal axis impacting fertility [3]
As of 2006, it was reported over 4 million men are impacted by hypogonadism in the United States [4]. Travison et al [5] first described hypogonadism can occur in younger men [6]. In fact, the average age of fathers has been consistently increasing since 1972. Specifically, fathers’ average ages have increased by 4.4 years over the past 45 years [7,8]. The combination of younger men being prescribed TRT and the average age of fathers increasing raises the importance of fertility preservation in men of reproductive age.
Intratesticular testosterone (ITT) is regarded as a critical component for spermatogenesis [9]. Unfortunately, ITT is decreased in men who receive TRT leading to impaired fertility potential. In recent years, 17-hydroxyprogesterone (17-OHP), an intermediate product of steroid metabolism, has been proposed as a surrogate biomarker for ITT and in turn, male fertility (Fig. 1) [7,10,11]. Existing evidence shows strong evidence of an inverse relationship between exogeneous TRT and serum 17-OHP along with an association between favorable semen parameters and increased 17-OHP serum levels [12]. As different TRT formulations have emerged in the market with each its own unique regimen schedule, it is unclear how each therapy impacts ITT. This study presents the first report of two open-label randomized control trials consisting of patients receiving either subcutaneous testosterone pellets (TP), intramuscular (IM), or intranasal testosterone (NT). We were able to quantify the differences each TRT formulation has on ITT using 17-OHP as a biomarker. We hypothesized that long-acting T formulations would decrease ITT compared to short-acting formulations due to short-acting T more closely mimicking the pulsatile secretion of gonadotropin-releasing hormone (GnRH).
Discussion
Usage of long-acting TRT in hypogonadal men was associated with a significantly decreased 17-OHP at follow-up. However, in line with the hypothesis, short-acting NT had the smallest change in 17-OHP following treatment compared to long-acting injectables or pellets. Our study is the first to simultaneously compare the impact of intranasal, intramuscular, and subcutaneous testosterone treatment on endogenous testosterone in hypogonadal males. The results of this study might suggest that short-acting formulations may have less of an impact on the local testicular environment
A plausible explanation for this finding is dosing schedule paired with the short half-life of NT more closely mimics normal physiology allowing for the maintenance of GnRH pulsatility (LH) and its downstream products luteinizing hormone and follicle-stimulating hormone (FSH) [13]. LH then stimulates Leydig cells within the testis to create endogenous testosterone that contributes to subsequent spermatogenesis. Given the increase of serum testosterone and maintenance of ITT, the result of this study should be considered when discussing the optimal TRT regimen for hypogonadal men who are concerned about testis atrophy and future fertility potential.
Long-acting testosterone has been shown to diminish endogenous testosterone production via suppression of the hypothalamic–pituitary–adrenal axis [14]. Men with low endogenous testosterone often suffer from decreased testes volume, and decreased sperm concentration with evidence of increased risk of all-cause and CVD death [15,16]. With an incidence of hypogonadism in 3% to 8% of 20 to 45-year-old men [9], and an average age of first-time fathers 31 years old [17] many hypogonadal males may be unwilling to begin treatment due to contraceptive effects from TRT. To date, physicians have countered this decrease in ITT by prescribing the LH-agonist human chorionic gonadotropin (HCG) to stimulate the testes to produce testosterone, and existing evidence shows sperm count recovery after TRT to 90% within 12 months [18]. However, the cost, lack of insurance coverage, and heavy restrictions imposed by the U.S. Food and Drug Administration (FDA) make HCG inaccessible for many. This study contributes to a clearer understanding of short-acting testosterone formulation's ability to maintain endogenous testosterone and supports previous research suggesting that intranasal testosterone gel can treat hypogonadism while maintaining semen parameters. There is a lack of information on whether hypogonadal men can recover endogenous testosterone production following TRT, and further studies should be done to evaluate this among the various delivery methods.
This study is not without limitations. While 17-OHP is helpful as a surrogate for ITT, it is an imperfect marker as approximately 30% is made by the adrenal glands. Future projects should be sure to include the collection of serum LH and FSH in subjects to better elucidate the pulsatility of GnRH between the various testosterone delivery methods. Given the retrospective study design, we are unable to quantify missed doses, medication non-adherence, nor the proficiency of the clinicians in counseling patients on TRT. In addition, while subjects were instructed regarding the timing of laboratory bloodwork their personal schedules or testing center availability may have precluded optimal profiling. Finally, our data only includes hypogonadal men recruited and treated at a single hospital system and may not be applicable to patients in different settings with replacement regimens beyond FDA recommendations [19-21]. Nevertheless, our study is the first to compare the impact of nasal, intramuscular, and subcutaneous testosterone treatment on 17-OHP in humans using randomized clinical trial data.
CONCLUSIONS
Short-acting nasal testosterone appears to have no impact on serum 17-OHP, especially in comparison to long-acting testosterone formulations. However, all TRT modalities demonstrated significant increases in serum testosterone levels of hypogonadal men at follow-up. Maintenance of 17-OHP gives insight into the testicular micro-environment which is especially important in spermatogenesis and overall male fertility. Intranasal T and other short-acting testosterone formulations may better to preserve ITT and be beneficial for hypogonadal men seeking to maintain fertility potential while on TRT.
