Impact of Short-Acting vs Long-Acting Testosterone Therapy on Intratesticular Testosterone Using Data From Two Open-Label Randomized Clinical Trials of Testosterone Pellets, Injections, and Intranasal Gel in Hypogonadal Men
Authors: Kresch Eliyahu , Gonzalez Daniel , Ory Jesse , Nackeeran Sirpi , Blachman-Braun Ruben , Molina Manuel , Ramasamy Ranjith 
Published: May 2021

Abstract
Introduction & Objective: Exogenous testosterone (T) replacement therapy (TRT) is typically long-acting and can potentially cause infertility in a majority of men due to suppression of HPG axis. Intratesticular testosterone is vital for spermatogenesis and can be reliably evaluated with serum 17-hydroxyprogesterone (17-OHP). Based on this observation, we hypothesized that we used serum 17-OHP as a serum biomarker for evaluating intratesticular T in men receiving TRT. We hypothesized that long-acting TRT will have a significant impact on suppressing HPG axis as compared to short-acting preparations. We evaluated data from two simultaneous open-label, randomized, two-arm clinical trials amongst different treatment preparations (Trial I) subcutaneous T pellets and (Trial II) Intranasal Testosterone (Natesto) or Intramuscular Testosterone cypionate (TC).
Subject & Methods: Hypogonadal men (2 AM serum T &lt; 300 ng/dL assayed by LC-MS/MS) aged 18-65 years were randomized into open-label randomized clinical trials. Eligible subjects received: 800mg subcutaneous Testopel T pellets (n=47); or 11mg TID Intranasal testosterone (Natesto) (n=10) or 200mg x 2 weeks TC (n=10) for 2 months. Serum T and 17-OHP were collected at baseline and after 2 months of therapy. Data are presented as a post-hoc analysis of the two randomized clinical trials and reported as the median and interquartile range [25th-75th], paired sample analysis (baseline versus follow-up) was performed with the Wilcoxon test to determine change during time within the different TRT modalities, with p&lt;0.05 considered significant.
Results: Median change for serum T between baseline and 2mo follow-up to subcutaneous T pellets was 542 [454-757] ng/dL, Intranasal Testosterone 706 [517-1010] ng/dL, and TC 525 [280-712]ng/dL.; 96% of subjects in each trial achieved mean T concentrations in the eugonadal range. We demonstrated that serum T levels were within normal range among men receiving the various therapies. As expected, we found a statistically significant decrease amongst the different T preparations in serum 17-OHP. Longer acting T preparations such as T pellets and TC demonstrated the greatest decrease in 17-OHP, from 41 [20.3-65.6] to 14 [10.3-20.8] ng/dL and 80 [48-121] ng/dL to 20 [17-36] ng/dL (p&lt;0.001), respectively. Shorter acting T preparations such as Natesto demonstrated a statistically significant decrease in 17-OHP, from 52.5 [26-67] ng/dL to 26.5 [18-39.8]ng/dL (p=0.007), but to a lesser extent as compared to the longer-acting preparations.
Conclusions: Natesto, and other short acting forms of TRT may help hyogonadal men maintain Intratesticular T that is critical for maintaining spermatogenesis. The differential effects of TRT on intratesticular T based on their half-lives is novel and should be considered during the decision making for hypogondal men who wish to preserve fertility and / or testis size.