Testosterone Undecanoate Research Articles

Effect of Testosterone Treatment for Delayed Puberty in Duchenne Muscular Dystrophy

Objective: To evaluate the impact of pubertal induction with testosterone on bone health, body composition, and motor function in boys with Duchenne muscular dystrophy (DMD) receiving long-term glucocorticoid. Study Design: A retrospective, observational, pre-post study investigating the impact of testosterone therapy on bone mass accrual, vertebral fracture incidence, body composition, motor function, and quality of life in boys with DMD. All those boys aged ≥14 years, on chronic steroid therapy, who had delayed puberty, and were receiving oral testosterone or oral and then transitioned to intramuscular testosterone, to complete virilization, were included. Prior/concomitant zoledronic acid use was included. The primary outcome was lumbar spine areal bone mineral density (BMD LS). Results: Puberty was induced, using oral testosterone undecanoate in 16 individuals, 10 of whom had transited to intramuscular testosterone at time of assessment. Median age at testosterone onset was 14.5 years (range 14–17.7). Median duration of testosterone therapy was 2.5 years (range 1.0–4.5). There was statistically significant increase in median BMD LS (0.523–0.700, p < 0.001) and median annualized percentage change of BMD LS (–1.34 to +10.08%, p < 0.001), with median Tanner stage 4 at evaluation (range 2–4). Ten of 14 assessed had no progression in vertebral fractures. Fat mass index (FMI) standard deviation score (SDS), lean body mass index (LBMI) SDS, and percentage change of FMI and LBMI were statistically unchanged. Cardiac function remained stable. Motor function in non-ambulatory individuals with Egen Klassifikation scores improved in 7 of 8. Conclusion: Testosterone for delayed puberty acted as an adjunct to bisphosphonates to increase bone density and stabilize vertebral fracture in most boys with DMD.

1057-P: Long-Term Testosterone Therapy Results in Remission of Type 2 Diabetes (T2DM) in 34.3% (61 of 178) Men with Hypogonadism and T2DM in a Real-World Registry Study

Background: In 2018, ADA Standards of Medical Care in Diabetes added measurement of testosterone levels in men with T2DM as new recommendation. Methods: A registry of men with hypogonadism (testosterone ≤12.1 nmol/L) was initiated in 2004 in a urological practice setting. 356 of 858 patients (41.5%) had T2DM diagnosed and treated in a diabetes center. Of these men, 178 received testosterone undecanoate (TU) injections 1000 mg/12 weeks (T-group) following an initial 6-week interval. Anthropometric and metabolic parameters were measured at least twice a year. Fasting insulin was used to calculate HOMA-IR. Results: After a mean follow-up of 7.7±3.0 (minimum 2, maximum 11 years), 61 patients (34.3%) were in remission, defined as discontinuation of all diabetes medications and stable HbA1c &amp;lt;6.5%. In men who went into remission, HbA1c dropped from 8.7±1.0% at baseline to 5.4±0.1% at the last measurement, HOMA-IR from 10.2±2.5 to 1.7±0.5. In men who never received insulin, HOMA%S increased from 11.1±1.5 to 15.8±2.4. Anthropometric parameters: Body weight declined progressively from 113.6±13.8 to 90.9±8.4 kg by 22.6±8.0 kg, waist circumference from 111.1±7.5 to 98.3±4.6 cm by 12.6±4.3 cm. All patients were on metformin at baseline. 22 patients were on insulin. The average observation time was 130.7±25.9 months (10.9±2.2 years). The average time to discontinuation of diabetes medication was 8.6±2.9 years, average follow-up after achieving remission 2.5±2.3 years. Medication adherence to TU was 100% as all injections were administered in the office and documented. PSA and hematocrit stayed within normal range during the entire observation period. Discussion: The effects of testosterone were likely mediated by sustained weight loss, increased lean body mass and a profound and sustained reduction of insulin resistance. Conclusions: Long-term testosterone treatment in men with hypogonadism may result in remission of T2DM. Disclosure K.S. Haider: None. A. Haider: None. F. Saad: Consultant; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Bayer AG. Funding Bayer AG

136-OR: Lipid Profile in Men with Hypogonadism and Type 2 Diabetes Improves during Long-Term Treatment with Testosterone Undecanoate Injections (TU) in Comparison to an Untreated Control Group: Update of Real-World Registry Data

Background: Previous studies reported inconsistent effects of testosterone therapy on the lipid profile in men with hypogonadism. Methods: Of 356 men with hypogonadism and T2DM, 178 received TU 1000 mg/12 weeks (T-group), 178 opted against treatment (CTRL). Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups. Results: Mean follow-up 8.2±2.9, baseline age 61.5±5.4 (T-group) and 63.7±4.9 (CTRL) years. Total cholesterol (mmol/L) decreased by 2.9±0.1 (from 8.3±1.1 to 5.2±0.3) at 11 years in T-group and increased by 1.1±0.1 (from 7.1±1.2 to 8.1±1.3) in CTRL. Estimated adjusted difference between groups: -4.0 (p&amp;lt;0.0001 for all). HDL (mmol/L) increased by 0.5±0.0 (from 1.0±0.4 to 1.6±0.4) in T-group and decreased by 0.3±0.0 (from 1.1±0.5 to 0.9±0.5) in CTRL, difference between groups: 0.8 (p&amp;lt;0.0001 for all). LDL (mmol/L) decreased by 1.9±0.1 (from 4.7±0.9 to 2.6±0.2) in T-group and increased by 0.9±0.1 (from 4.1±1.4 to 4.9±1.5) in CTRL, difference between groups: -2.8 (p&amp;lt;0.0001 for all). Triglyceride (mmol/L) decreased by 1.1±0.0 (from 3.5±0.6 to 2.2±0.1) in T-group and increased by 0.5±0.0 (from 3.1±0.6 to 3.7±0.6) in CTRL, difference between groups: -1.7 (p&amp;lt;0.0001 for all). Non-HDL (mmol/L) decreased by 5.5±0.3 (from 9.6±4.3 to 3.4±0.8) in T-group and increased by 4.9±0.3 (from 8.0±3.9 to 11.3±6.8) in CTRL, difference between groups: -10.4 (p&amp;lt;0.0001 for all). Remnant cholesterol (mmol/L) decreased by 1.4±0.1 (from 2.6±1.0 to 1.0±0.2) in T-group and increased by 0.5±0.1 (from 2.0±1.0 to 2.3±0.7) in CTRL, difference between groups: -1.9 (p&amp;lt;0.0001 for all). Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM progressively improved the lipid profile, which worsened in controls. Disclosure F. Saad: Consultant; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Bayer AG. K.S. Haider: None. A. Haider: None. Funding Bayer AG

Testosterone replacement therapy of opioid-induced male hypogonadism improved body composition but not pain perception: a double-blind, randomized, and placebo-controlled trial.

Hypogonadism is prevalent during opioid treatment, but the effect of testosterone replacement treatment (TRT) on body composition, pain perception, and adrenal function is unclear. To measure changes in body composition, pain perception, quality of life, and adrenal function after TRT or placebo in opioid-treated men with chronic non-malignant pain. Double-blind, placebo-controlled study in 41 men (>18 years) with total testosterone <12 nmol/L were randomized to 24 weeks TRT (Testosterone undecanoate injection three times/6 months, n = 20) or placebo (placebo-injections, n = 21). Body composition (lean body mass and fat mass assessed by DXA), clinical pain intensity (numerical rating scale), and experimental pain perception (quantitative sensory assessment), quality of life (SF36), and adrenocorticotrophic hormone (ACTH) test. Data were presented as median (quartiles). Mann-Whitney tests were performed on delta values (24-0 weeks) between TRT and placebo. The median age was 55 years (46; 59) and total testosterone before intervention was 6.8 (5.0; 9.3) nmol/L. TRT was associated with change of testosterone levels: 12.3 (7.0; 19.9) nmol/L (P < 0.001 vs placebo), increased lean body mass: 3.6 (2.3; 5.0) kg vs 0.1 kg (-2.1; 1.5) during TRT vs placebo and decreased total fat mass: -1.2 (-3.1; 0.7) kg vs 1.2 kg (-0.9; 2.5) kg, both P < 0.003. Changed pain perception, SF36, and ACTH-stimulated cortisol levels were non-significantly changed during TRT compared with placebo. Six months of TRT improved body composition in men with opioid-induced hypogonadism without significant changes in outcomes of pain perception, quality of life, or adrenal function.

2004-P: Treatment with Testosterone Undecanoate Injections (TU) Results in Marked Weight Loss That Is Maintained Long Term in Men with Hypogonadism and Type 2 Diabetes (T2DM): Update of Real-World Data from a Urological Practice

Background: The prevalence of hypogonadism is particularly high in men with obesity and T2DM. Methods: Of 356 men with hypogonadism and T2DM, 288 (80.9%) were obese, 61 (17.1%) overweight and 7 (2.0%) had normal weight. 178 received TU 1000 mg/12 weeks (T-group) following an initial 6-week interval, 178 opted against treatment (CTRL). Changes over time between groups were compared and adjusted for age, weight, WC, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between groups. Results: Mean baseline age: 62.6±5.2 years, mean follow-up: 8.2. T-group: weight decreased by 22.1±0.5 kg at 11 years. CTRL: weight increased by 6.8±0.5. Estimated adjusted difference between groups: 28.9 kg (p&amp;lt;0.0001 for all). T-group: WC decreased by 13.3±0.4 cm. CTRL: WC increased by 7.1±0.4 cm. Difference between groups: 20.4 cm (p&amp;lt;0.0001 for all). T-group: BMI decreased by 7.3±0.2 kg/m². CTRL: BMI increased by 2.2±0.2 kg/m². Difference between groups: 9.5 kg/m² (p&amp;lt;0.0001 for all). There was a weight loss of 19.3±0.4% in the T-group and weight gain of 7.4±0.4% in CTRL, difference between groups: 26.7% (p&amp;lt;0.0001 for all). Waist:height ratio decreased by 0.08±0.00 in the T-group and increased by 0.04±0.00 in CTRL, difference between groups: 0.12 (p&amp;lt;0.0001 for all). Visceral adiposity index (VAI) decreased by 3.0±0.2 in the T-group and increased by 3.2±0.2 in CTRL, difference between groups: 6.2 (p&amp;lt;0.0001 for all). Since injections were administered in the office and documented, there was a 100% adherence to testosterone therapy. Conclusions: Treatment with testosterone undecanoate injections results in profound weight loss that is maintained long-term with continued testosterone therapy. Disclosure A. Haider: None. K.S. Haider: None. F. Saad: Consultant; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Bayer AG. Funding Bayer AG

1075-P: Long-Term Treatment with Testosterone Undecanoate Injections (TU) Improves Glycemic Control in Patients with Hypogonadism and Type 2 Diabetes (T2DM): Update of Real-World Data with 2,928 Patient-Years

Background: Prevalence of hypogonadism has been reported as high as 50% in men with T2DM. ADA Guidelines recommend assessment of hypogonadism in men with T2DM. Methods: In a registry of 858 men with hypogonadism, 356 men (41.5%) had T2DM. 178 received TU 1000 mg/12 weeks (T-group), 178 opted against treatment (CTRL). Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups. Results: Mean follow-up 8.2±2.9, baseline age: 61.5±5.4 (T-group) and 63.7±4.9 (CTRL) years. T-group: HbA1c progressively decreased by 3.4±0.1% at 11 years (from 9.4±1.4% to 5.8±0.3%). CTRL: HbA1c increased by 3.3±0.1% (from 7.8±0.7% to 10.5±1.4%). Estimated adjusted difference between groups: 6.7% (p&amp;lt;0.0001 for all). Fasting glucose (mmol/L) decreased in T-group by 1.8±0.1 (from 7.8±1.2 to 5.4±0.1) and increased in CTRL by 1.7±0.1 (from 6.3±0.7 to 8.0±1.6). Difference between groups: 3.6 (p&amp;lt;0.0001 for all). In the T-group, 87 men (48.9%) received insulin at baseline at a mean dose of 37.8±13.4 U/d. Dose requirement declined by 25.9±1.1 U/d during the observation period. In CTRL, 69 men (38.8%) received insulin at baseline at a mean dose of 31.3±6.2 U/d. Dose requirement increased by 19.3±1.1 U/d. Difference between groups: 45.2 U/d (p&amp;lt;0.0001 for all). In men who never received insulin (91 in T-group, 89 in CTRL), HOMA-IR decreased from 9.8±2.0 to 2.3±0.6 by 7.0±0.3 (T-group) and increased from 7.1±1.3 to 12.8±1.9 by 5.4±0.3 (CTRL). Difference between groups: 12.4 (p&amp;lt;0.0001 for all). In CTRL, 20 patients were started on insulin during the observation period. Conclusions: Long-term testosterone therapy with TU in men with hypogonadism and T2DM progressively improved glycemic control which deteriorated in untreated men. Disclosure F. Saad: Consultant; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Bayer AG. K.S. Haider: None. A. Haider: None. Funding Bayer AG

401-P: Mortality, Major Adverse Cardiovascular Events (MACDE), and Diabetic Complications in Men with Hypogonadism and Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Testosterone Undecanoate Injections (TU): 11-Year Real-World Data

Background: Men with hypogonadism are at increased risk of MACE and mortality. Studies in men with T2DM show that testosterone therapy (TTh) reduces both MACE and mortality. Methods: In a registry of 858 men with hypogonadism, 356 men (41.5%) had T2DM. 178 received testosterone undecanoate injections (TU) 1000 mg/12 weeks (T-group) and 178 opted against treatment (CTRL). MACE, mortality, and diabetic complications were recorded and compared between groups. Results: Mean baseline age in the T-group and CTRL was 61.8±5.1 and 63.6±4.9 years, respectively. Mean follow-up in T-group vs. CTRL was 7.4 and 8.3 years, respectively. 69 patients (38.8%) in the T-group and 70 (39.3%) in CTRL had a history of cardiovascular disease (myocardial infarction, stroke, or coronary artery disease diagnosis) (p=0.9135). Baseline smoking prevalence was 41.6% (74 men) in the T-group and 38.2% (68 men) in CTRL (p=0.5161). The T-group had significantly worse baseline risk factor profile than CTRL: BMI (36.5±4.5 vs. 33.4±5.3 kg/m²), systolic blood pressure (163.0±13.3 vs. 145.6±14.6 mmHg), LDL (4.7±0.9 vs. 4.1±1.4 mmol/L), HbA1c 9.4±1.4 vs. 7.8±0.7% (p&amp;lt;0.0001 for all). Mortality: during the entire observation period, 13 patients (7.3%) died in the T-group vs. 48 (27.0%) in CTRL (p&amp;lt;0.0001). MACE: in the T-group, there were no cases of myocardial infarction or stroke. In CTRL, there were 55 cases of myocardial infarction (30.9%) and 45 cases of stroke (25.3%). Diabetic complications: in the T-group vs. CTRL, the incidence of retinopathy was 3.4% and 16.9% (p&amp;lt;0.0001), nephropathy 0.6% and 4% (p&amp;lt;0.05), polyneuropathy 6.2% and 54.8% (p&amp;lt;0.0001), diabetic foot syndrome 0% and 9.6% (p&amp;lt;0.0001). Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM significantly reduces MACE and mortality, as well as diabetic complications compared to untreated controls. Disclosure A. Haider: None. K.S. Haider: None. F. Saad: Consultant; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Bayer AG. Funding Bayer AG

1058-P: Effects of Treatment with Testosterone Undecanoate Injections (TU) on Estimated Glomerular Filtration Rate (eGFR) in Men with Hypogonadism and Type 2 Diabetes Mellitus (T2DM) Compared with an Untreated Control Group: Real-World Data

Background: Reduced eGFR is associated with increased risk of cardiovascular disease and mortality. Methods: In a urological practice registry of 858 men with hypogonadism, 356 men (41.5%) had T2DM. 178 received TU 1000 mg every 12 weeks (T-group). 178 opted against treatment (CTRL). Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the groups. eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula. Results: Mean follow-up 8.2±2.9, baseline age: 61.5±5.4 (T-group) and 63.7±4.9 years (CTRL). Creatinine decreased by 0.16±0.03 mg/dL at 11 years in the T-group and increased by 0.32±0.03 mg/dL in CTRL. Estimated adjusted difference between groups: -0.48 mg/dL (p&amp;lt;0.0001 for all). T-group: eGFR increased by 9.8±1.4 mL/min/1.73 m². The peak mean value was recorded in year 8 after which a small but steady decline occurred. CTRL: eGFR decreased progressively by 22.3±1.3 mL/min/1.73 m². Difference between groups: 32.2 mL/min/1.73 m² (p&amp;lt;0.0001 for all). Systolic blood pressure decreased in the T-group by 32.3±1.2 mmHg and increased in CTRL by 14.5±1.1 mmHg. Difference between groups: -46.8 mmHg (p&amp;lt;0.0001 for all). Diastolic blood pressure decreased in the T-group by 19.2±0.9 mmHg and increased in CTRL by 9.5±0.8 mmHg. Difference between groups: -28.7 mmHg (p&amp;lt;0.0001 for all). During the entire observation period, 13 deaths (7.3%) and no cardiovascular events occurred in the T-group. In CTRL, 48 deaths (27.0%), 55 cases of myocardial infarction (30.9%) and 45 cases of stroke (25.3%) were recorded. Nephropathy occurred in 0.6% in the T-group and in 4% in CTRL (p&amp;lt;0.05). Conclusions: Long-term testosterone therapy in men with hypogonadism and T2DM prevents age-related deterioration in GFR. Disclosure K.S. Haider: None. A. Haider: None. F. Saad: Consultant; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Bayer AG. Funding Bayer AG

Impact of testosterone treatment on circulating irisin in men with late-onset hypogonadism and metabolic syndrome

Objectives The beneficial effects of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH) on the body composition and metabolic outcomes are well-established. A potential explanation might lie in the hormones, secreted from skeletal muscles, named “myokines". The aim of this study was to evaluate the effects of TRT on the levels of serum irisin in subjects with LOH. Study Design A total 40 men with metabolic syndrome (MS) and LOH (measured serum testosterone concentration < 12 nmol/l). TRT with Testosterone Undecanoate (Nebido™) was performed at baseline and at week 6. Irisin serum concentration was determined at baseline and at week 18 by means of ELISA. Results Circulating irisin was positively associated with serum testosterone (r = 0.283, p < 0.05). TRT has led to a statistically significant rise in circulating serum irisin levels (7.12 ± 0.76 mcg/ml versus 7.76 ± 0.75 mcg/ml; paired-samples t-test p < 0.001). ROC-analyses determined irisin to be predictive of treatment response (AUC = 0.741, p = 0.014). Conclusions Irisin is positively associated with serum testosterone in a population of men with MS and LOH. TRT in these subjects has led to a significant improvement in associated clinical symptoms as well as to a significant rise in serum irisin levels.

SAT-LB6 First Human Trial of an Oral Native Testosterone Shows Physiological Levels of Testosterone and Dht in Both Fasted and Fed State in Hypogonadal Men

Introduction: The prevalence of male hypogonadism is estimated to be 6% in the USA (1). Current therapies have limited acceptability: gels can be messy and risk inadvertent dosing of others; injections are painful; and oral testosterone undecanoate (TU) delivers variable testosterone levels, requires concurrent ingestion of a fatty meal and may produce supraphysiological dihydrotestosterone (DHT) levels. We present the first human trial of an oral native testosterone preparation formulated to deliver physiological levels of testosterone irrespective of food intake. Aim: To compare the pharmacokinetics of DITEST (Diurnal Ltd Cardiff, UK) to an oil based oral TU formulation (Andriol Testocaps MSD, UK) and explore the effect of food on DITEST bioavailability. Methods: Single centre, phase 1b study of DITEST in 25 adult males with hypogonadism, one subject withdrawn after single period and only included in safety analysis (Clinicaltrials.gov: NCT02966652). Part 1 compared the pharmacokinetics of 80mg TU with 120mg DITEST after a high fat meal. Part 2 the pharmacokinetics of 200mg of DITEST administered in either fed or fasted states. Results are baseline adjusted. Results: DITEST showed a testosterone dose response between 120mg and 200mg with Cmax 550 (19.1) and 877 (30.4) ng/dl (nmol/l) and AUC0-10h 59.5 and 88.6 h*nmol/L. DITEST 200mg gave an equivalent Cmax and AUC0-10h to TU 80mg: Cmax 877 (30.4) vs 906 (31.4) ng/dl (nmol/l) and AUC0-10h 88.6 vs 102 h*nmol/L. Fed and fasted DITEST had similar pharmacokinetics: Cmax 764 (26.5) vs 877 (30.4) ng/dl (nmol/L), AUC0-10h 87.0 vs 88.6. DITEST resulted in lower levels of DHT than TU: Cmax 84 (2.9), 131 (4.5) & 194 (6.7) ng/dl (nmol/l); AUC0-10h 11.0, 16.7 & 36.3 h*nmol/L for DITEST 120mg, 200mg & 80mg TU, respectively. There was one serious adverse event (urinary retention) in the study during TU dosing. There were no emerging safety concerns, and adverse event frequency and severity was similar between the two treatments. Discussion: These results demonstrate that 200mg DITEST provides similar testosterone exposure with more physiological DHT exposure than 80mg TU given with a high fat meal. Administration of DITEST in fed and fasted states provides similar testosterone and DHT exposure. Compared to published literature on a self-emulsifying formulation of TU at 200mg, DITEST at 200mg provides a similar testosterone Cmax and no requirement for a fatty meal (2). Conclusion: DITEST is an oral native testosterone formulation with anticipated advantages over current oral therapy of dosing without food and a lower risk of supraphysiological DHT levels.

SUN-046 Prevalence of Polycythaemia with Different Formulations of Testosterone Therapy in Transmasculine Individuals

Background: Masculinising hormone therapy with testosterone is used to align an individual’s physical characteristics with their gender identity. Testosterone therapy is typically administered via intramuscular or transdermal routes and polycythaemia is the most common adverse event. Aims: To compare the risk of polycythaemia with different formulations of testosterone therapy in transmasculine individuals. Methods: A retrospective cross-sectional analysis was undertaken of transmasculine individuals at a primary and secondary care clinic in Melbourne, Australia. 180 individuals who were on testosterone therapy for >6 months were included. Groups included those receiving (1) intramuscular testosterone undecanoate (n=125), (2) intramuscular testosterone enantate (n=31), or (3) transdermal testosterone (n=24). Outcome was prevalence of polycythaemia (defined as haematocrit >0.5). Results: Mean age was 28.4 (8.8) years with a median duration of testosterone therapy 37.7 (24.2) months. 27% were smokers. There was no difference between groups in serum total testosterone concentration measured. Whilst there was no difference between groups in haematocrit, there was a higher proportion of patients with polycythemia in those who were on intramuscular testosterone enantate (23.3%) than on transdermal testosterone (0%), p=0.040. There was no statistically significant difference in polycythaemia between intramuscular testosterone undecanoate (15%) and transdermal, p=0.066 nor between intramuscular testosterone enantate and undecanoate, p=0.275. Conclusions: One in four individuals treated with intramuscular testosterone enantate and one in six treated with testosterone undecanoate had polycythaemia. No individual treated with transdermal testosterone had polycythaemia. This highlights the importance of regular monitoring of haematocrit in transmasculine individuals treated with testosterone and findings may inform treatment choices.

SAT-038 Ambulatory Blood Pressure Increases in Hypogonadal Men Who Develop Increases in Hematocrit on Oral Testosterone Undecanoate

There is concern that testosterone replacement therapies might increase blood pressure (BP) with chronic use. Testosterone undecanoate is a novel oral testosterone therapy under development for the treatment of male hypogonadism. We studied the effects of testosterone undecanoate (225 mg twice daily) on ambulatory blood pressure (ABP) and heart rate, in 138 men with hypogonadism (mean age, 54 years, 79% white, 48% with a history of hypertension). Ambulatory BP and heart rate and hematologic parameters were obtained at baseline and following 4 months of daily therapy. Changes from baseline in ambulatory 24-hour, awake, and sleep systolic BP of 3.8 (p=0.06), 5.2 (p=0.01), and 4.3 mmHg (p=0.07) were observed post-treatment, respectively. Smaller changes in the diastolic BP were observed (1.2 (p=0.13), 1.7 (p=0.04), and 1.7 mmHg (p=0.11) for 24-hour, awake, and sleep, respectively). Changes in the 24-hour, awake and sleep heart rates were 1.9 (p=0.07), 2.6 (p=0.02), and 0.4 (p=0.68) beats/minute respectively. There were no significant differences in changes from baseline in the 24-hour ambulatory BP for the 57 subjects who had a medical history of hypertension versus the 61 subjects who did not have hypertension: 4.5/1.5 mmHg in the hypertension subgroup versus 3.2/0.9 mmHg in the non-hypertensive subgroup (p = 0.53/0.46 between groups). Hematocrit and hemoglobin increased by 3.2% and 0.9 g/dl in all subjects after 4 months of therapy. In those men in the top quartile of changes in hematocrit (corresponding to upper / lower boundary increases of 6 and 14% with 9.3% achieving levels > 52%), the largest increases in ambulatory systolic BP (8.3 mmHg) were observed, whereas the changes in ambulatory systolic BP in the lower 3 quartiles were substantially smaller (1.6, 3.2, and 2.7 mmHg in quartiles 1, 2 and 3 of hematocrit change, respectively). In conclusion, these data demonstrate increases in ambulatory BP occurred following 4 months of oral testosterone undecanoate, particularly in those men whose hematocrit rose by > 6% or whose resultant hematocrit was 52% or higher. Hence, hematocrit maybe a useful clinical parameter that could effectively predict the risk of developing increases in BP on oral testosterone undecanoate.

SAT-044 Treatment of Hypogonadal Men with a New Oral Testosterone Undecanoate (TU) Formulation Improves Psychosexual, Well-Being and Body Composition and Bone Density Parameters

Introduction and Objective: A new, first-in-class oral testosterone (T) replacement therapy product [T-undecanoate (TU) capsules] was recently approved by FDA to treat hypogonadal men. Clinical trials were conducted to evaluate, in part, the impact of oral TU therapy on important secondary efficacy endpoints: Psychosexual and/or general well-being (Trial I and II); and body composition and bone mineral density (BMD) (Trial II). Subject and Methods: Hypogonadal men (AM serum T ≤ 300 ng/dL) age 18 to 65 (Trial I) or 75 years old (Trial II) were randomized into open-label, active-comparator (T-gel/solution) trials. Subjects received: Trial 1: Oral TU (n=166) or a topical T solution (n=55) for 4-6 mos.; or Trial II: Oral TU (n=162) or T-gel (n=163) for 12 mos. The starting oral TU dose (with food) was 237 mg, BID in Trial I and 316 mg, BID in Trial II; up to 2 dose-titration opportunities were available to achieve eugonadal T concentrations (assayed by LC-MS/MS). In Trial I, Psychosexual Daily Questionnaires (PDQ) were completed by study subjects for 7 days at baseline and prior to final clinic visit (Day 105-180). In Trial II, the SF-36 well-being questionnaire was completed on Days 0, 30, 90, 180, 270 and 365 and PDQs were completed for 7 days prior to clinic visits on these same days. In Trial II body composition and BMD was assessed by DEXA scan on Days 0, 180 and 365. Safety was monitored by physical exam and standard clinical lab tests. Results: Mean serum T in response to oral TU was 489 ± 155 ng/dL (mean ± SD) (Trial I) and 628 ± 342 ng/dL (Trial II); 84% of subjects in each trial achieved mean T concentrations in the eugonadal range. Statistically significant mean changes from baseline (p<0.0001) for most SF-36 well-being parameters were observed in both oral TU and T-gel groups. Psychosexual questionnaire results also demonstrated statistically significant improvement over baseline (p<0.0001) in most parameters at Day 30 and all timepoints thereafter in both trials. On Days 180 and 365 (v. baseline) oral TU was associated with a significant reduction in fat mass [-1.92 ± 2.79 (SD) and -2.4 ± 3.6 kg, respectively] (p<0.0001) and an increase in lean body mass [+2.87 ± 2.73 and +3.15 ± 2.69 kg, respectively] (p<0.0001). Oral TU increased mean BMD over baseline on Days 180 and 365 in spine [+0.013 ± 0.035 and +0.018 ± 0.042 g/cm2, respectively (p<0.0001)] and hip [+0.006 ± 0.019 and +0.012 ± 0.023 g/cm2, respectively (p<0.0001)]. Oral TU exhibited a safety profile consistent with commonly prescribed topical T-comparators. Modest increases in cuff sBP of 2.8 ± 11.84 (SD) mm Hg and 1.8 ± 10.76 mm Hg were observed in Trial I for both oral TU and the comparator T-solution. Conclusions: Treatment of hypogonadal men with oral TU yielded circulating mean T concentrations in the mid-eugonadal range and significantly improved psychosexual, general well-being, body composition and BMD parameters comparable to transdermal T administration.

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.

SUN-LB114 Remission of Type 2 Diabetes (DMT2) in Hypogonadal Men Under Long-Term Testosterone Therapy

Objective: The increasing prevalence of DMT2 and obesity represents a growing clinical and health-care cost problem. These two pathologies simultaneously increase the risk of hypertension, myocardial infarction, stroke or venous thromboembolism. An existing but undetected testosterone deficiency will substantially hamper weight loss or render it impossible. In such cases, returning the testosterone level to normal range is therefore the necessary pre-condition to fight obesity and thus the related comorbidities. Materials and methods: 35 obese (waist circumference (WC) > 94 cm) men aged 48 [33;57] with diagnosed DMT2 (IDF 2019 criteria), hypogonadism (ISSAM 2015 criteria) and vitamin D deficiency (Endocrine Society Guidelines 2014 criteria) were treated with testosterone undecanoate (1000 mg 4 mL injected i.m. every three months following an initial 6-week interval), cholecalciferol 5. 000-10.000 IU per day. 29 patients received 1000-2000 mg per day, 1 patient received liraglutide 1,8 mg a day + metformin 1500 mg a day, 1 patient received Sitagliptin 100 mg and metformin 1000 mg a day. 4 patients did not use anti-diabetic treatment ever. The duration of follow up was 36 months. Waist circumference (WC, cm), glucose (mmol/L), HbA1c (%), total testosterone (nmol/L) and vitamin D (25(OH)D3, ng/mL) were assessed at baseline and after 36 months of follow up. Statistical research was made using a software package statistics (StatSoft Inc. U.S., version 6.0). Quantitative data are presented as medians and quartile range. When comparing the quantitative data of two groups Wilcoxon test was used. Values were considered statistically significant if p <0.05. Results: All patients had no DMT2 diagnostic criteria after 24 months of treatment. WC changed from 107 [102;116] to 94 [88.5;97.5], HbA1c from 7,2 [6.9;7,7] to 5,7 [5.25;5.8], TT from 7.37 [6.2;9.18] to 24.65 [22.3;25.9], 25(OH)D3 from 20.2 [11.7;26.2] to 72 [65;88] at baseline and after 24 months of follow up, respectively. All changes were statistically significant. Anti-diabetic therapy was cancelled in all patients after 20,5 [15;24] months of follow up. All patients remained under further follow up for the period up to 36 months, no cases of DMT2 recurrence were registered.Conclusion: We conclude that correction of testosterone and vitamin D deficiency may work as a necessary stimulus for consequential facilitation of weight reduction and associated recovery, particularly in terms of a complete remission of diabetes. Long term data is needed.

SAT-049 Testosterone Therapy Reduces Inflammatory Activation of Human Monocytes in Hypogonadal Type-2 Diabetic Men as a Potential Mechanism to Improve Atherosclerosis

Testosterone deficiency is prevalent in men with type 2 diabetes (T2D) and is associated with greatly elevated risk of cardiovascular mortality. Testosterone replacement has beneficial effects on surrogate markers and risk factors of atherosclerosis including inflammation, cholesterol and insulin resistance improving survival in men with T2D. The underlying mechanisms of this action remain poorly understood. Inflammation is a central feature to both T2D and atherosclerosis and is driven by monocyte/macrophages, placing these immune cells at the crossroads of disease pathology. The recruitment of immune cells to atherosclerosis-prone areas of the vasculature is influenced by many factors including the inflammatory status of the circulating monocytes. The present study investigates the influence of testosterone replacement on monocyte inflammatory markers in a randomised double blinded placebo controlled clinical trial. 65 men with poorly controlled diabetes (HbA1c between 53 and 80 mmol/mol) and confirmed hypogonadism via early morning [0800−1200h] total testosterone ≤12 nmol/L or calculated free testosterone ≤255 pmol/L on two occasions ≥1 week apart, with at least two symptoms of hypogonadism were included in the study. Patients were randomly assigned to either placebo or treatment (depot testosterone undecanoate, 6 weekly followed by 3 monthly intramuscular injections) for 6 months. Monocytes were isolated from whole blood collected at baseline, 3 and 6 month visits followed by gene expression of key inflammatory targets IL-1β, IL-6, IL-10, TNFα, ICAM1, TLR2, TLR4, SCARB1 and MCP1 assessed via qPCR. Pro-inflammatory targets TNFα and MCP1 were significantly reduced over time in monocytes from patients treated with testosterone between 3 and 6 months (1.39±0.39 Vs 0.68±0.09, P<0.01; 15.36±7.79 Vs 1.88±0.93, P<0.01 respectively) and TNFα at 6 months compared to the start of the study (1.00±0.00 Vs 0.68±0.09, P<0.001) when normalised to baseline. TNFα expression was also significantly reduced compared to placebo treated patient monocytes at 6 months (0.68±0.09 Vs 3.45±1.50, P<0.01). Other targets were not significantly altered over time or between treatment groups. These findings importantly indicate for the first time that testosterone influences monocyte inflammatory activation in type 2 diabetic men by altering expression of the most potent atherogenic chemokine MCP1 and potent pro-inflammatory cytokine TNFα, as a potential mechanism to protect against atherosclerotic plaque development in hypogonadism.

SAT-051 Effects of Testosterone Replacement on Glycemic Control and Other Cardiovascular Risk Factors in Hypogonadal Men with Uncontrolled Type 2 Diabetes (Stride Study): Design, Implementation and Baseline Data

Up to 40% of men with type II diabetes are testosterone deficient. There is growing evidence that testosterone therapy has a beneficial effect on glycemic control, insulin resistance and may have a cardioprotective effect, contrary to the traditional view that testosterone is detrimental to the heart. Our study aims to evaluate the effect of testosterone therapy on glycaemic control other cardiovascular risk factors, symptomatic benefit and quality of life in a randomised double-blind placebo controlled add-on of testosterone therapy to their normal hypoglycemic medication in hypogonadal men with uncontrolled type 2 diabetes. The study population includes 65 eligible men (140 screened) with poorly controlled diabetes (HbA1c between 53 and 80 mmol/mol) and confirmed hypogonadism by early morning [0800−1200h] total testosterone [TT] ≤12 nmol/L or calculated free testosterone ≤255 pmol/L on two occasions ≥1 week apart, with at least two symptoms of hypogonadism. The trial is divided into 2 phases. Phase 1: patients are randomly assigned to either treatment (depot testosterone undecanoate) arm or the placebo arm for 6 months. Phase 2: open label phase for 6 months with subjects on placebo on placebo initiated on to testosterone therapy while subjects in the treatment group continue to receive treatment for the 12 month duration. No change to anti- glycaemic therapy was made during the first phase of the study. The primary endpoint is HbA1c. Secondary endpoints include body composition (bioelectrical impedence DEXA scan), HOMA-IR, lipid profile, blood pressure (24 hr BP monitor), carotid media intima thickness, monocyte mRNA cytokine expression, Questionnaires include AMS (Aging Male Symptom Score), IIEF-5(International Index of Erectile Dysfunction), SF36-Quality of life, Mini mental score, New questionnaire for hypogonadism in diabetes (to be validated), NERI (New England Research Institute) hypogonadal screener. Baseline data indicate the mean age 59 (42-77) years. Mean Duration of diabetes was 8.6(0-21) years. 18 men were on Insulin. The remaining 47 men were either diet controlled or on oral hypoglycaemic medications. 9 men had pre-existing history of MI and 4 had history of angina. Mean HbA1c at baseline was 65(53-80) mmol/mol. Mean total testosterone level was 8.9(2.1-16.9) nmol/l. Mean weight and BMI at baseline were 107(71-187) kg and 34.5(24-52) respectively. Mean waist circumference was 115.7(46-160) cm The primary aim of this is to determine if testosterone therapy improves glycemic control in men with uncontrolled diabetes. Secondly to assess beneficial effects on specific cardiovascular parameters as well as QOL. This could have a major clinical implication on how we treat patients with hypogonadism and type 2 diabetes.

SAT-745 Lower Serum Estradiol Levels in Assigned Female at Birth Transgender People with Initiation of Testosterone Therapy: Results from the European Network for the Investigation of Gender Incongruence (ENIGI)

Introduction: Aromatization of exogenous testosterone might result in increased estradiol levels. Concerns have been raised about undesired estrogenic effects in assigned female at birth (AFAB) transgender people. How serum estradiol levels change after initiation of testosterone therapy and if these levels should be monitored, remains unclear. Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Serum levels of sex steroids were assessed in 746 AFAB transgender people during a three-year follow-up period, starting at the initiation of hormone treatment. Results: Estradiol levels decreased from median [P25-P75] 45.5[24.0-102.2]pg/mL to 36.5[25.0-46.2]pg/mL over three years (P<0.001), a change was already noticeable during the first three months (mean - 17.1 pg/mL, 95% CI -23.8 - -10.6, P<0.001). Serum estradiol levels were lower in people without endogenous estradiol production (contraceptive users or post gonadectomy) at baseline and after three months, compared to people with endogenous estradiol production. Using long acting testosterone undecanoate injections resulted in a more prominent decrease in serum estradiol values over twelve months, compared to short acting mixed testosterone esters (P<0.001) or testosterone gel (P=0.001). Changes in serum estradiol were positively correlated to changes in LH (ρ = 0.107, P<0.001) and negatively correlated to changes in FSH levels (ρ=-0.167, P<0.001) and body mass index (ρ=-0.082, P<0.001). Conclusion: Testosterone administration in AFAB transgender people results in decreasing serum estradiol levels. Although an underlying mechanism for the observed decrease in serum estradiol levels remains difficult to fathom, our results suggest that testosterone administration suppresses endogenous estradiol production. The exception found in people without endogenous estradiol production may be attributed to aromatization of exogenous testosterone.

Development and validation of a fast gas chromatography combustion isotope ratio mass spectrometry method for the detection of epiandrosterone sulfate in urine.

In doping control, to confirm the exogenous origin of exogenously administered anabolic androgenic steroids (AAS), a gas chromatography combustion isotope ratio mass spectrometry (GC-C-IRMS) analysis is performed. Recently published work suggests that epiandrosterone sulfate (EpiAS) is a promising IRMS target compound for the detection of AAS, capable of prolonging the detection window. However, EpiAS is only excreted in urine in its sulfoconjugated form, while all other IRMS target compounds are excreted glucuronidated, meaning that EpiAS cannot be incorporated in the existing IRMS methods. A separate extensive sample preparation needs to be performed on this compound with a different hydrolysis and extraction procedure and a different liquid chromatography (LC) clean-up. The current work presents a new, fast, and easy to implement EpiAS IRMS method. The approach was based on the direct GC analysis of non-hydrolyzed EpiAS, making the solid phase extraction, hydrolysis, and acetylation step redundant. Sample preparation consisted of a simple liquid-liquid extraction, followed by LC fraction collection. A population study was performed to check compliance with the criteria drafted by the World Anti-Doping Agency (WADA). To verify the applicability of the developed approach, the method was applied to the samples of four administration studies (i.e. dehydroepiandrosterone (DHEA), testosterone gel (T gel), androstenedione (ADION), and intramuscular testosterone undecanoate. In contrast to previously published data, the strength of EpiAS as the target compound and the prolongation of the detection window in comparison with the conventional IRMS target compounds was less pronounced.

MP45-02 POPULATION PHARMACOKINETIC MODELING AND SIMULATION TO ASSESS THE IMPACT OF AN 8-WEEK MAINTENANCE DOSING REGIMEN FOR INTRAMUSCULAR TESTOSTERONE UNDECANOATE

INTRODUCTION AND OBJECTIVE: Intramuscular (IM) testosterone undecanoate (TU) is indicated for testosterone (T) replacement in adult males with a deficiency or absence of endogenous T. IM TU is currently approved to be administered at initiation and at 4 weeks (wks) followed by a maintenance dose every 10 wks (750 mg/dose). However, a more frequent maintenance regimen (every 8 wks) may improve the management of symptoms of low T at the end of each dosing interval. The objective of this work was to develop a population pharmacokinetic (popPK) model for IM TU and to perform PK simulations to assess the impact of an 8-wk maintenance regimen on T exposures. METHODS: A popPK model was developed to characterize the PK of serum total T using data from 130 hypogonadal men receiving the approved 10-wk maintenance regimen of IM TU in Study IP157-001 Part C. T profiles were then simulated for 8-wk and 10-wk maintenance regimens (10 doses/regimen) based on the population size and demographics of Study IP157-001 Part C. Using simulated T concentrations, the following parameters were calculated: average concentration (Cavg), maximum concentration (Cmax), and trough concentration (Ctrough). Responder rates of clinical interest were determined for each parameter. RESULTS: The PK of TU was well-described by a 1-compartment model with 1st-order absorption and elimination kinetics. The model included a rapid suppression and gradual recovery of endogenous T production during TU administration. Lower clearance (CL/F) and volume of distribution (V/F) were associated with lower body weight, more rapid IM absorption with lower body weight, and greater CL/F with lower sex hormone binding globulin levels. Simulated T PK profiles and responder rates for Dose 10 are presented in Figure 1. Improved responder rates for Cavg and Ctrough were predicted for the 8-wk regimen compared to the 10-wk regimen with no increase in Cmax excursions >2500 ng/dL. CONCLUSIONS: Simulations indicate that the absolute percent of Ctrough responders (Ctrough >300 ng/dL) increased by 9.4% (95% confidence interval: 8.5% – 10.3%) for the 8-wk regimen compared to the 10-wk regimen. Smaller impacts of the 8-wk regimen were calculated for Cavg and Cmax with no increase in Cmax excursions >2500 ng/dL for the 8-wk regimen.Source of Funding: Endo Pharmaceuticals Inc.