T Replacement Therapy Research Articles

PMON267 Comparison Between Single Time Point Testing and 24-Hour Average Concentration of Total Testosterone in Hypogonadal Men Treated with an Oral Testosterone Undecanoate Softgel (JATENZO®)

Abstract In 2019, a novel, first-in-class testosterone (T) replacement therapy (TRT), oral testosterone undecanoate (TU) was approved by the U.S. FDA for the treatment of male hypogonadism. During clinical trials, dose adjustments were based on 24-hr average T concentration (Cavg) because single T measurements were considered less accurate. Subsequent, concordance analyses for this oral TU product have shown that a single total T value 6-hrs after the morning oral TU dose best corresponds to Cavg. Nonetheless, a conversion factor for T values obtained at other post-dose time points would be useful for healthcare providers (HCPs) and ease potential scheduling challenges for patients. Consequently, the relationship between other T sampling time points and Cavg was examined to determine if a reliable conversion factor could be derived to help HCPs monitor a patient's serum T concentration at times other than 6-hrs after oral TU administration. Hypogonadal men, age 18–65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. Overall, 166 men were randomized into the oral TU arm. Dose titration was based on Cavg calculated from serial pharmacokinetic (PK) samples. There were three pre-designated PK visits, to individualize the appropriate TU dose and to achieve a eugonadal T Cavg by the final study visit. Ratios between different timepoints and Cavg were determined for PK samples following morning drug administration. Overall, 87.3% (95% CI: 81.3%, 92.0%) of hypogonadal men had a final Cavg in the eugonadal range, with a mean serum total T = 488.7 ± 154.5 ng/dL (16.95 ± 5.37 nmol/L). Pooled values from all PK days demonstrated a linear relationship between T concentrations at 4, 6, and 9-hrs and Cavg (p < 0.0001). Visit and time of sampling interaction were not statistically significant (p >> 0.50), indicating consistency in results among PK visits and among sampling timepoints. A factor was derived to enable conversion of T values assessed at a time other than 6-hrs (post oral TU dose) into a close approximation of Cavg: 1/[1.870–0.14×(hours after AM dose)]. Therefore, a sample drawn at 4-hrs after the morning oral TU dose would be multiplied by 0.75; while one drawn at 8-hrs would be multiplied by 1.33. Hence, T Cavg can be approximated after morning JATENZO administration if a blood sample cannot be collected precisely 6-hrs thereafter. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Two-year administration data of an oral testosterone undecanoate (TU) formulation in hypogonadal men

ABSTRACT Introduction An oral testosterone (T) replacement therapy (TRT) would be the preferred administration route for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men with two-year follow up. Methods Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results Overall, 86 subjects participated in both studies. T concentration increased from 193.75 ± 9.44 ng/dL (Mean ± SEM) at baseline (BL) to 475.5 ± 49.7 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests – ALP (64.05 ± 1.95 to 53.74 U/L ± 1.86 U/L), ALT (27.8 ± 1.40 to 26.7 ± 1.6 U/L), AST (21.6 ± 0.76 to 22.0 ± 1.0 U/L), and bilirubin (0.58 ± 0.03 to 0.52 ± 0.03 mg/dL) throughout the two studies. At d270, one subject had an ALT level of 227 U/L, which was > 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on d290, and the level dropped to 87 U/L, < 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. Although there was a slight increase in prostate-growth related endpoints, there were no significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (44.3 ± 0.3 to 46.6 ± 0.5%, p < 0.001) and cuff systolic BP (127.1 ± 1.2 to 131.8 ± 1.67 mmHg vs BL, p = 0.006). The change in CV endpoints, including HDL-C, hematocrit, and BP, changed initially and stabilized throughout the 2 trials. For example, systolic BP varied 3 – 6 mm Hg from BL throughout the study. Conclusion This oral TU formulation is an option for hypogonadal men and has a safety profile consistent with other approved T products, such as a rise in hematocrit and a decrease in HDL-C. Notably, no evidence of liver toxicity was observed over 2 years. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children. Disclosure Work supported by industry: yes, by Clarus Therapeutics. A consultant, employee (part time or full time) or shareholder is among the authors (Clarus Therapeutics).

Abstract #1184225: Linear Relationship Between Time of Testing and 24-Hour Average Concentration of Total Testosterone in Hypogoandal Men Treated with an Oral Testosterone Undecanoate Softgel (JATENZO®)

In 2019, a novel, first-in-class testosterone (T) replacement therapy (TRT), oral testosterone undecanoate (TU) was approved by the US FDA for the treatment of male hypogonadism. Individualized dosing is based on 24-hr average concentration (Cavg). For this oral TU product, concordance studies have shown that total T at 6 hrs after the morning oral TU dose best corresponds to Cavg. Unfortunately, testing at 6 hrs may pose scheduling difficulties. To ease potential schedule issues, the relationship between other assay time points and Cavg was examined to determine if a conversion factor could be derived to help clinicians monitor patient’s serum T concentrations.

MP35-09 LINEAR RELATIONSHIP BETWEEN THE TIME OF DOSING AND 24-HOUR AVERAGE CONCENTRATION OF TOTAL TESTOSTERONE IN MEN TREATED WITH AN ORAL TESTOSTERONE UNDECANOATE CAPSULE (JATENZO®)

You have accessJournal of UrologyCME1 May 2022MP35-09 LINEAR RELATIONSHIP BETWEEN THE TIME OF DOSING AND 24-HOUR AVERAGE CONCENTRATION OF TOTAL TESTOSTERONE IN MEN TREATED WITH AN ORAL TESTOSTERONE UNDECANOATE CAPSULE (JATENZO®) Ronald Swerdloff, Jason Kovac, Christina Wang, Marc Gittelman, B. Woun Seo, Jay Newmark, Nestor Rohowsky, and Robert Dudley Ronald SwerdloffRonald Swerdloff More articles by this author , Jason KovacJason Kovac More articles by this author , Christina WangChristina Wang More articles by this author , Marc GittelmanMarc Gittelman More articles by this author , B. Woun SeoB. Woun Seo More articles by this author , Jay NewmarkJay Newmark More articles by this author , Nestor RohowskyNestor Rohowsky More articles by this author , and Robert DudleyRobert Dudley More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002589.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In 2019, a novel, first-in-class testosterone (T) replacement therapy (TRT), oral testosterone undecanoate (TU) was approved by the US FDA for the treatment of male hypogonadism. Concordance studies have shown that total T at 6 hrs after the morning TU dose best corresponds to the total T 24-hr average concentration (Cavg). Hence, product labeling directs clinicians to measure serum T 6 hrs after a morning TU dose. However, testing at 6 hrs may pose scheduling difficulties for some men. Therefore, the relationship between other T assay time points and Cavg was examined to see if a conversion factor could be derived to convert T values collected at earlier or later times than directed in product labeling (i.e., 6 hrs) into values that reflect true Cavg. METHODS: Hypogonadal men, age 18–65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. Dose titration was based on Cavg calculated from serial pharmacokinetic (PK) samples. Patients had two dose adjustments based Cavg. Because of the need for titration, there were three different PK visits. Ratio between the different timepoints and Cavg were determined for the oral TU PK samples following morning drug administration. RESULTS: With the values from all three PK days pooled, there was a linear relationship between T concentrations at 4, 6, and 9 hrs and Cavg (r2=0.35). The r2 for the three visits were similar: 1st PK visit, r2=0.33; 2nd PK visit, r2=0.36; final PK visit, r2=0.35. A factor based on the following equation was derived to enable conversion of T values assessed at a times other than 6 hrs (i.e., time of blood draw) into a close approximation of Cavg: (1.870−0.14)×(hours after AM dose). Table summarizes the conversion factors to normalize T to Cavg at various T assay time points. To illustrate, for a serum T value drawn at either 4 or 8 hrs after the morning oral TU dose, the normalized (or corrected) Cavg concentration would be approximately 75% or 133% of the drawn value, respectively. CONCLUSIONS: While dose titration for this novel oral TRT is based on a serum T level drawn at 6 hours after the AM dose, the T level can be estimated from samples obtained at other timepoints using a conversion factor. Source of Funding: Clarus Therapeutics © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e590 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ronald Swerdloff More articles by this author Jason Kovac More articles by this author Christina Wang More articles by this author Marc Gittelman More articles by this author B. Woun Seo More articles by this author Jay Newmark More articles by this author Nestor Rohowsky More articles by this author Robert Dudley More articles by this author Expand All Advertisement PDF DownloadLoading ...

Real-World Experience with First FDA-Approved Oral Testosterone Undecanoate Formulation

ABSTRACT Introduction The diagnosis of hypogonadism (HG) in men requires both consistently low testosterone (T) levels and signs and symptoms of T deficiency. Management of HG with T replacement therapy (TRT) aims to improve both low serum T levels and patients’ symptomatic complaints. The first oral softgel formulation of testosterone undecanoate (TU) was recently approved by FDA (JATENZO®) for TRT in men with specific hypogonadal conditions and is available in 3 capsule strengths and 5 dosage combinations for necessary dose adjustments. However, dose titration may not be necessary in many patients treated with this new oral TU formulation given the wide eugonadal range. Objective Assess the ability of any given daily dosage of oral TU to restore T to eugonadal levels without dose adjustment at steady state (Css); and determine real-world dose titration experience of patients treated with oral TU. Methods Pharmacokinetic (PK) simulations were performed using a robust population PK model developed for T in 474 hypogonadal men who were treated with oral TU in prior PK studies. The model consisted of a 1-compartment model with absorption lag time and an allometric function on key allometric parameters to account for differences in body weight. This final population PK model was coded in Trial Simulator v2.3.0.6 software. T levels were simulated following oral TU BID dosing on Day 55 (i.e., at steady state) with no dose adjustments. Average T concentrations (Cavg) were derived from multiple serial blood samples collected over 24 hrs for oral TU doses of 237, 316, and 396 mg TU, BID (without dose modification). The percent of subjects with T levels within the eugonadal range (serum Cavg between 304 ng/dL-1030 ng/dL) at each of these TU dose levels was calculated. Prescription data was also accessed in the Symphony PatientSource Patient Transactional Dataset to evaluate the frequency of real-world dose titration. Results The percentage of subjects with Css T Cavg within the eugonadal range for 237, 316, and 396 mg TU, BID were 61%, 74% and 74%, respectively. These corresponded to mean [5%, 95% CI] serum T levels (ng/dL) of 398 [389, 406], 560 [549, 572] and 728 [715, 741] ng/dL, respectively. Early assessment of real-world prescribing data for JATENZO indicated 35% of patients underwent dose titration by month 5. Conclusions Simulated daily BID dosing of oral TU without dose adjustment yielded eugonadal T levels in most subjects at all 3 dose levels examined. These data are consistent with initial early real-world experience with oral TU that indicates dose titration has not been required in most patients. However, because the desired outcome of TRT therapy focuses on both T Cavg and symptomatic response, this oral TU formulation enables necessary dose adjustment when needed. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics, Inc. Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics, Inc.

Two-Year Administration Data of an Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men

ABSTRACT Introduction An oral testosterone (T) replacement therapy (TRT) would be the preferred administration route for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. Objective The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men with two-year follow up. Methods Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results Overall, 86 subjects participated in both studies. T concentration increased from 193.75 ± 9.44 ng/dL (Mean ± SEM) at baseline (BL) to 475.5 ± 49.7 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests – ALP (64.05 ± 1.95 to 53.74 U/L ± 1.86 U/L), ALT (27.8 ± 1.40 to 26.7 ± 1.6 U/L), AST (21.6 ± 0.76 to 22.0 ± 1.0 U/L), and bilirubin (0.58 ± 0.03 to 0.52 ± 0.03 mg/dL) throughout the two studies. At d270, one subject had an ALT level of 227 U/L, which was > 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on d290, and the level dropped to 87 U/L, < 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. Although there was a slight increase in prostate-growth related endpoints, there were no significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (44.3 ± 0.3 to 46.6 ± 0.5%, p < 0.001) and cuff systolic BP (127.1 ± 1.2 to 131.8 ± 1.67 mmHg vs BL, p = 0.006). The change in CV endpoints, including HDL-C, hematocrit, and BP, changed initially and stabilized throughout the 2 trials. For example, systolic BP varied 3 – 6 mm Hg from BL throughout the study. Conclusions This oral TU formulation is an option for hypogonadal men and has a safety profile consistent with other approved T products, such as a rise in hematocrit and a decrease in HDL-C. Notably, no evidence of liver toxicity was observed over 2 years. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics

Testosterone supplementation and bone parameters: a systematic review and meta-analysis study.

The role of testosterone (T) replacement therapy (TRT) in subjects with late onset hypogonadism is still the object of an intense debate. All observational studies and placebo-controlled or -uncontrolled randomized trials (RCTs) comparing the effect of TRT on different bone parameters were considered. Out of 349 articles, 36 were considered, including 3103 individuals with a mean trial duration of 66.6weeks. TRT improves areal bone mineral density (aBMD) at the spine and femoral neck levels in observational studies, whereas placebo-controlled RTCs showed a positive effect of TRT only at lumber spine and when trials included only hypogonadal patients at baseline (total testosterone < 12nM). The effects on aBMD were more evident in subjects with lower T levels at baseline and increased as a function of trial duration and a higher prevalence of diabetic subjects. Either T or estradiol increase at endpoint contributed to aBMD improvement. TRT was associated with a significant reduction of bone resorption markers in observational but not in controlled studies. TRT is able to inhibit bone resorption and increase bone mass, particularly at the lumbar spine level and when the duration is long enough to allow the anabolic effect of T and estrogens on bone metabolism to take place.

IMPACT OF TESTOSTERONE THERAPY ON POLYCYTHEMIA: EVALUATION OF DATA FROM TWO ONGOING OPEN-LABEL RANDOMIZED SINGLE-CENTER CLINICAL TRIALS

Testosterone (T) replacement therapy (TRT) is the mainstay treatment for male hypogonadism. The most commonly reported adverse event among men using TRT is polycythemia. What is unknown is whether the short-acting vs. long-acting testosterone preparations have different effects on hematocrit. We hypothesized that short-acting testosterone therapy will be physiologic and have lesser effect on hematocrit compared to long-acting TRT. We evaluated data from two simultaneous ongoing open-label, randomized, two-arm clinical trials to evaluate the impact of TRT on Hematocrit and compared prevalence rates of polycythemia among subcutaneous T pellets (long-acting) and Intranasal Testosterone or Intramuscular Testosterone cypionate (TC) (short-acting).

MP31-08 EXOGENOUS TESTOSTERONE THERAPY IN MEN WITH KLINEFELTER SYNDROME NEGATIVELY IMPACTS SPERM RETRIEVAL

You have accessJournal of UrologyInfertility: Therapy (MP31)1 Sep 2021MP31-08 EXOGENOUS TESTOSTERONE THERAPY IN MEN WITH KLINEFELTER SYNDROME NEGATIVELY IMPACTS SPERM RETRIEVAL Caroline Kang, Nahid Punjani, and Peter N. Schlegel Caroline KangCaroline Kang More articles by this author , Nahid PunjaniNahid Punjani More articles by this author , and Peter N. SchlegelPeter N. Schlegel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002035.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Men with Klinefelter syndrome (KS) classically have testicular failure and are at risk for both testosterone (T) deficiency and infertility. T replacement therapy (TRT) often is initiated in adolescence for its potential neurodevelopmental benefits. Unfortunately, exogenous T has a defined adverse effect on spermatogenesis. We sought to examine the effect of exogenous T on sperm retrieval in men with KS. METHODS: All men with KS undergoing sperm retrieval by microdissection testicular sperm extraction (mTESE) performed by a single surgeon between 1995-2020 were reviewed. Demographic data and hormone-modifying agents, such as human chorionic gonadotropin (hCG) and aromatase inhibitors (AI), administered prior to mTESE were obtained. History or current use of exogenous T was recorded and categorized based on formulation into either short- (gel or foam) or long-acting (pellets or injection) groups. Descriptive statistics and SRR are reported. Patients with incomplete data on hormone therapy as well as repeat procedures on the same patient were excluded. RESULTS: A total of 290 sperm retrievals were performed on KS men during the study period. Fourteen men had a history of exogenous TRT or were currently using T at time of mTESE (Table 1). Median age was 34 years (interquartile range (IQR) 31–36), and median testis size was 1.3 mL (IQR 1.0–1.5). Five men had a remote history of TRT up to 2 years prior to mTESE, and received hCG and AI hormone therapy prior to retrieval. Of these, all five (100%) had successful sperm retrieval. In five men receiving topical testosterone and concurrent AI and/or hCG at time of mTESE, only two (40%) had successful sperm retrieval. No men receiving continuous delivery of exogenous testosterone (e.g., injectable or pellet) with concurrent hCG had sperm identified during mTESE. CONCLUSIONS: Exogenous TRT is common in KS patients. Long-acting (e.g. injectable or implantable T) therapy suppresses gonadotropin production and sperm production, predisposing men to failed sperm retrieval. However, T monotherapy with short-acting (e.g. topical) formulations together with AIs can maintain endogenous gonadotropin production and spermatogenesis; such therapy is consistent with sperm retrieval in KS men. Additional prospective trials are needed to elucidate the effects of T on sperm retrieval in KS patients. Source of Funding: CK and NP are supported in part by the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e557-e558 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Caroline Kang More articles by this author Nahid Punjani More articles by this author Peter N. Schlegel More articles by this author Expand All Advertisement Loading ...

PD20-07 SAFETY ANALYSIS OF AN ORAL TESTOSTERONE UNDECANOATE (TU) FORMULATION FOLLOWING 2 YEARS OF ADMINISTRATION IN HYPOGONADAL MEN

INTRODUCTION AND OBJECTIVE:An oral testosterone (T) replacement therapy (TRT) would be the preferred administration route for many hypogonadal men. Until recently, the only oral TRT approved in the...

Impact of Testosterone Therapy on Hematocrit and Polycythemia: Evaluation of Data From Two Ongoing Open-Label Randomized Single-Center Clinical Trials

Introduction & Objective: Testosterone (T) replacement therapy (TRT) is the mainstay treatment for male hypogonadism. The most commonly reported adverse event among men using TRT is polycythemia. What is unknown is whether the short-acting vs. long-acting testosterone preparations have different effects on hematocrit. We hypothesized that short-acting testosterone therapy will be physiologic and have lesser effect on hematocrit compared to long-acting TRT. We evaluated data from two simultaneous ongoing open-label, randomized, two-arm clinical trials to evaluate the impact of TRT on Hematocrit and compared prevalence rates of polycythemia among subcutaneous T pellets (long-acting) and Intranasal Testosterone (Natesto) or Intramuscular Testosterone cypionate (TC) (short-acting). Subject and Methods: Hypogonadal men (2 AM serum T < 300 ng/dL assayed by LC-MS/MS) aged 18-65 years were randomized into open-label randomized clinical trials. Eligible subjects received: Trial 1: 800mg subcutaneous Testopel T pellets; Trial 2: 11mg TID Intranasal testosterone (Natesto) or 200mg x 2 weeks TC for 2 months. Serum T, Hematocrit (HCT), and prevalence of polycythemia (as defined as HCT >50%) 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 median and interquartile range [25th-75th], paired sample analysis (baseline versus follow-up) was performed with the Wilcoxon rank test to determine change during time within the different TRT modalities, with p<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. T pellets showed a statistically significant increase in HCT from 44.6 [42.0-46.6] to 46.7 [42.6-48.9] (p<0.001), with a prevalence of 7/47 (14%) men developing polycythemia. A safety trigger for HCT greater than 54% occurred in 2/47 (4%). The treatment effect was independent of baseline serum testosterone. TRT with Natesto decreased HCT, from 43.4 [41.6-46.1] to 43.4 [40.6-46.5], however not statistically significant (p=0.262). TC statistically increased HCT from 41.6 [40.3-43.1] to 43.8 [43.5-47.4] (p=0.018), with 0% of men developing polycythemia in both groups. Conclusions: Long acting TRT appears to increase hematocrit compared to short-acting testosterone therapies. Treatment of hypogonadal men with Intranasal T Natesto and testosterone cypionate successfully achieved target serum T level and maintained HCT levels. Longer-term durability and safety effects of the intervention remain to be further investigated.

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

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 < 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<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<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.

Safety Analysis of an Oral Testosterone Undecanoate (TU) Formulation Following 2 Years of Administration in Hypogonadal Men

Introduction: An oral testosterone (T) replacement therapy (TRT) would be the preferred choice for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men for up to 2 years. Subjects and Methods: Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results: Overall, up to 81 subjects were available for evaluation. T concentration increased from 208.3 ± 102.4 ng/dL (Mean ± SD) at baseline (BL) to 470.1 ± 396.5 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests - ALT (28.0 ± 12.3 to 26.6 ± 12.8 U/L), AST (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL) throughout the two studies. At Day 270, one subject had an ALT level of 227 U/L, which was > 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on Day 290, and the level dropped to 87 U/L, < 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. There were not any significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (+2.52 ± 3.7% vs BL, p < 0.001) and cuff systolic BP (+5.6 ± 15.0 mmHg vs BL, p = 0.006). The change in prostate-related growth variables and CV endpoints changed initially and stabilized throughout the 2 trials. For example, systolic BP consistently showed a mean increase from BL between 3 - 6 mmHg. Conclusion: This oral TU formulation is an effective long-term therapy for hypogonadal men and has a safety profile consistent with other approved T products. Notably, no evidence of liver toxicity was observed. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children.

Leydig cell aging: Molecular mechanisms and treatments.

Late-onset hypogonadism, resulting from deficiency in serum testosterone (T), affects the health and quality of life of millions of aging men. T is synthesized by Leydig cells (LCs) in response to luteinizing hormone (LH). LH binds LC plasma membrane receptors, inducing the formation of a supramolecular complex of cytosolic and mitochondrial proteins, the Steroidogenic InteracTomE (SITE). SITE proteins are involved in targeting cholesterol to CYP11A1 in the mitochondria, the first enzyme of the steroidogenic cascade. Cholesterol translocation is the rate-determining step in T formation. With aging, LC defects occur that include changes in SITE, an increasingly oxidative intracellular environment, and reduced androgen formation and serum T levels. T replacement therapy (TRT) will restore T levels, but reported side effects make it desirable to develop additional strategies for increasing T. One approach is to target LC protein-protein interactions and thus increase T production by the hypofunctional Leydig cells themselves.

Effect of testosterone on lipid metabolism and endothelium in men with type 2 diabetes mellitus and hypogonadism

Abstract Background To date, knowledge about the effects of testosterone (T) on the cardiovascular system of men remains controversial and requires additional research. Especially the putative impact of T replacement therapy (TRT) on lipid metabolism and endothelial dysfunction as a starting mechanism for the development of cardiovascular pathology in men with type 2 diabetes mellitus (T2DM) presenting with T deficiency has to be elucidated. The aim of this work was to evaluate the effect of T replacement therapy on lipid metabolism and function of endothelium in men with T2DM and hypogonadism. Methods The study included 95 men (mean age 55,3±2,4 years) with T2DM and late onset hypogonadism, established according to EAU 2015 criteria. Parameters of carbohydrate and lipid metabolism, as well as ultrasound assessment of flow-mediated dilatation of the brachial artery (FMD-BA) and intima-media thickness (IMT) of brachial arteries were performed at baseline and after 9 months. Patients were randomized into 2 groups: 1 - 45 men receiving TRT, using 1% transdermal T-gel and 2 (control group) - 50 men, who were not assigned to TRT. Statistical analysis was carried out using the Wilcoxon - test for repeated measurements (STATISTICA 10 software package). Results During the treatment period no serious adverse events were registered. The study revealed a significant decrease in HbA1c (p&amp;lt;0.001), total cholesterol (p=0.009), triglycerides (p=0.004) and LDL (p=0.01) levels as well as an increase in HDL level (p=0.001) in the 1st group vs baseline and compared to the 2nd one. There was a decrease in IMT (from 1.0 [0.8; 1.1] to 0.7 [0.6; 0.9] mm, p=0.002) in the 1st group compared to the 2nd (p&amp;lt;0.001). The endothelium-dependent FMD-BA increased 1.5 - fold in men applying T-Gel vs baseline as well as compared to the control group at the time point of follow- up (p&amp;lt;0.001). At the same time TRT leaded to acceleration of the time until maximal vasodilation – it became twice faster (from 120 [90; 120] to 60 [60; 90] sec, p&amp;lt;0.001) compared to baseline and the 2nd group (p&amp;lt;0.001). Linear blood flow velocity increased markedly in the 1st group compared to the 2nd at the time point of follow-up (p=0.03). Conclusion TRT in men with T2DM and T deficiency leads to an improvement in carbohydrate and lipid metabolism together with a significant decrease in IMT and enhancement of endothelium vasomotor function, seems to facilitate a reduction in cardiovascular risk. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Russian Science Foundation

Late-onset hypogonadism: Reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy.

Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late-onset hypogonadism (LOH). To review the mechanism by which TRT could damage the cardiovascular system. Comprehensive literature search of recent clinical and experimental studies. The mechanisms of T-mediated coronary vasodilation were reviewed with emphasis on calcium-activated and ATP-sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3-kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via β1-adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase-2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in TNF-α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO-triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed. The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors. Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed.

Controversial aspects of testosterone in the regulation of sexual function in late-onset hypogonadism.

Testosterone (T) plays a pivotal role in coordinating a series of psychological, cognitive and physical events that might (or might not) culminate in male sexual activity. In fact, T deficiency is associated, in a statistically significant way, with several sexual dysfunctions including erectile dysfunction (ED), reduction of spontaneous erection and hypoactive sexual desire (HSD). Although these associations are statistically significant, there is debate if they are also clinically meaningful. In addition, sexual dysfunctions are present also in several metabolic conditions - such as type 2 diabetes mellitus and obesity - that often associate with low T. In particular, this is the case of ED, but not of HSD, that, therefore, should be considered a more genuine correlate of T deficiency in adulthood and aging (late-onset hypogonadism, LOH). The aim of this review is to scrutinize evidence from our and other studies on sexual effects of T replacement therapy (TRT) in LOH. We will use preclinical and clinical data coming from our and other laboratories and meta-analyses. Intervention studies in clinical trials involving subjects with LOH, and their meta-analyses, indicate that TRT is able to ameliorate HSD, spontaneous erection and ED. However, the relative improvement of ED by TRT is marginal [2-3 points of International Index of Erectile Function-erectile function domain (IIEF-EFD)] and significantly smoothed in subjects with the aforementioned metabolic conditions. In LOH, positive effects of TRT on other domains of sexual activity, such as orgasm and sexual satisfaction, are also apparent in the different meta-analyses. Hence, TRT is a reasonable treatment for restoring sexual drive in LOH, with some additional positive effects also on erection (spontaneous and sexual-related) and on orgasm. In contrast, preclinical and clinical studies indicate that T administration to eugonadal subjects does not improve male sexual activity.

SAT-052 A Novel Oral Testosterone Therapy (TLANDO) Safely Restores Testosterone to Eugonadal Levels with Fixed Dose Treatment

Most testosterone (T) replacement therapy (TRT) products have relied on dose titration to achieve eugonadal levels. However, dose titration in clinical practice can be time-consuming, expensive, and subject to errors. TLANDO (LPCN 1021) is a novel oral testosterone undecanoate (TU) product absorbed via the intestinal lymphatic pathway. A previous clinical study (NCT02081300) suggested that titration with TLANDO has little to no impact to improve PK profiles. The objective of this study was to assess whether fixed dose of TLANDO can restore testosterone to eugonadal levels. A 24 day, open-label, single-arm, multicenter study with TLANDO in hypogonadal men (NCT03242590) was conducted. Subjects (N=95) received 225 mg testosterone undecanoate orally twice a day (i.e., 30 minutes after morning and evening meals) for 24 days. On Day 24, blood samples were collected over a 24 hour period. The primary endpoint was the percentage of TLANDO-treated subjects who achieved a 24-hour average serum T concentration within the eugonadal range of 300 to 1080 ng/dL after 24 days of treatment. Mean peak serum T concentration was calculated based on daily TLANDO administration at Day 24. Key safety endpoints included incidence of adverse events (AEs), physical examination results, clinical laboratory test results, and changes in HCT, lipids, and PSA. Treatment compliance was calculated as a percentage of the amount of study drug used divided by the amount of study drug expected to be used. 94 subjects completed the study with mean age of 56.0 years, mean BMI 32.8 kg/m2, and baseline T level 202 ± 75 ng/dL. 80% of subjects achieved a 24-hour average serum T concentration within the normal range at Day 24. The lower and upper bounds of the 95% confidence interval was 72% and 88% respectively. Following daily administration of TLANDO at Day 24, the mean peak serum T concentration was 1178 ± 484 ng/dL. The incidence of treatment emergent adverse events (TEAEs) was 21%. The most frequently reported TEAEs were blood prolactin increase (6.3%), weight increase (2.1%), headache (2.1%), and musculoskeletal pain (2.1%). No deaths were reported during the study. Increase in hematocrit (0.9%) and PSA (0.2 μg/L) was observed. Decrease in lipids was observed (-6.9 mg/dL for HDL, -1.5 mg/dL for LDL, -8.9 mg/dL for triglycerides, and -10.6 mg/dL for total cholesterol). Overall mean treatment compliance was 99.7 ± 4.9%. In conclusion, a twice-daily, fixed-dose of TLANDO (450 mg TU total daily dose) successfully achieved target serum T level and achieved a safety profile consistent with that of other approved TRT products.

Obstructive Sleep Apnea Is Associated With Polycythemia in Hypogonadal Men on Testosterone Replacement Therapy

BackgroundPolycythemia (erythrocytosis) is a known side effect of testosterone (T) replacement therapy (TRT) and appears to correlate with maximum T levels. There is also a well-established association between obstructive sleep apnea (OSA) and the development of polycythemia, which confers additional long-term cardiovascular morbidity. Synergy between TRT and OSA in the development of polycythemia remains poorly understood. AimThe objective of this study was to retrospectively assess the relationship of OSA and secondary polycythemia in hypogonadal men receiving TRT. MethodsWe performed a retrospective chart review of all men treated by a single provider from 2015 to 2019 for the diagnosis of hypogonadism. Patients who developed a hematocrit of 52% or greater were classified as having polycythemia. OSA was identified via clinical documentation or use of nocturnal continuous positive airway pressure. Demographics, laboratory values, treatment details, and comorbidities were recorded. Data were reported as mean ± SD for parametric variables and median [interquartile range] for non-parametric values. OutcomeThe primary outcome of this study was the association between OSA and polycythemia in hypogonadal men on TRT. Results474 men were included in this study. 62/474 (13.1%) men met the criteria for the diagnosis of polycythemia with a median hematocrit of 53.6 [interquartile range 52.6, 55.5]. Univariate analysis demonstrated a strong positive association between polycythemia and the concomitant diagnosis of OSA in hypogonadal men (P = .002). Even after correcting for age, body mass index (BMI), and peak T levels in the multivariate analysis (P = .01), this relationship remained significant with an odds ratio of 2.09 [95% CI 1.17, 3.76]. 37 men on TRT with polycythemia and OSA were included in the final cohort with a mean age of 59.2 ± 11.4 years, mean BMI of 32.4 ± 6.0, and median time from TRT initiation to polycythemia diagnosis of 3 years. All patients diagnosed with OSA were prescribed continuous positive airway pressure with poor compliance noted in 52.8% of men. 37.8% were managed via phlebotomy and 59.5% were managed via dose de-escalation of TRT. In hypogonadal men on TRT with polycythemia, BMI was the only risk factor strongly associated with OSA (P = .013). Clinical TranslationIn hypogonadal men (particularly those with elevated BMI) on TRT who develop secondary polycythemia, a diagnosis of OSA should be strongly considered. Strengths & LimitationsThis is a single provider retrospective study and further studies are needed to assess generalizability. ConclusionsIn this retrospective single-center cohort, the development of polycythemia in hypogonadal men on TRT was associated with an increased prevalence of OSA.Lundy SD, Parekh NV, Shoskes DA. Obstructive Sleep Apnea Is Associated With Polycythemia in Hypogonadal Men on Testosterone Replacement Therapy. J Sex Med 2020;17:1297–1303.

MP45-15 A NOVEL ORAL TESTOSTERONE THERAPY RESTORES TESTOSTERONE TO EUGONADAL LEVELS WITHOUT DOSE TITRATION

INTRODUCTION AND OBJECTIVE:Most testosterone (T) replacement therapy (TRT) products have relied on dose titration to achieve eugonadal T range. However, dose titration in clinical practice can be t...