Pharmacokinetics and Acceptability of Subcutaneous Injection of Testosterone Undecanoate.

CONTEXT: Can injectable testosterone undecanoate (TU) be administered effectively and acceptably by the subcutaneous (SC) route? OBJECTIVE: To investigate the acceptability and pharmacokinetics (PK) of SC injection of TU. DESIGN: Randomized sequence, crossover clinical study of SC vs IM TU injections. SETTING: Ambulatory clinic of an academic andrology center. PARTICIPANTS: Twenty men (11 hypogonadal, 9 transgender men) who were long-term users of TU. injections. Intervention: Injection of 1000 mg TU (in 4 mL castor oil vehicle) by SC or IM route. Main Outcome Measures: Patient-reported pain, acceptability, and preference scales. PK by measurement of serum testosterone, dihydrotestosterone (DHT), and estradiol (E2) concentrations with application of population PK methods and dried blood spot (DBS) sampling. RESULTS: Pain was greater after SC compared with IM injection 24 hours (but not immediately) after injection but both routes were equally acceptable. Ultimately 11 preferred IM, 6 preferred SC, and 3 had no preference. The DBS-based PK analysis of serum testosterone revealed a later time of peak testosterone concentration after SC vs IM injection (8.0 vs 3.3 days) but no significant route differences in model-predicted peak testosterone concentration (8.4 vs 9.6 ng/mL) or mean resident time (183 vs 110 days). The PK of venous serum testosterone, DHT, and E2 did not differ according to route of injection. CONCLUSIONS: We conclude that SC TU injection is acceptable but produces greater pain 24 hours after injection that may contribute to the overall majority preference for the IM injection. The PK of testosterone, DHT, or E2 did not differ substantially between SC and IM routes. Hence whereas further studies are required, the SC route represents an alternative to IM injections without a need to change dose for men for whom IM injection is not desired or recommended.

Urinary Sex Steroids and Anthropometric Markers of Puberty - A Novel Approach to Characterising Within-Person Changes of Puberty Hormones.

BACKGROUND/AIMS: The longitudinal relationships of within-individual hormone and anthropometric changes during puberty have not ever been fully described. The objectives of this study were to demonstrate that 3 monthly urine collection was feasible in young adolescents and to utilise liquid chromatography-tandem mass spectrometry assay methods for serum and urine testosterone (T), estradiol (E2) and luteinizing hormone (LH) in adolescents by relating temporal changes in urine and serum hormones over 12 months to standard measures of pubertal development. METHODS: A community sample of 104 adolescents (57 female) was studied over 12 months with annual anthropometric assessment, blood sampling and self-rated Tanner staging and urine collected every 3 months. Serum and urine sex steroids (T, E2) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LH by immunoassay. RESULTS: A high proportion (92%) of scheduled samples were obtained with low attrition rate of 6.7% over the 12 months. Urine hormone measurements correlated cross-sectionally and longitudinally with age, anthropometry and Tanner stage. CONCLUSION: We have developed a feasible and valid sampling methodology and measurements for puberty hormones in urine, which allows a sampling frequency by which individual pubertal progression in adolescents can be described in depth.

Requirement for specific gravity and creatinine adjustments for urinary steroids and luteinizing hormone concentrations in adolescents.

OBJECTIVES: Urinary hormone concentrations are often adjusted to correct for hydration status. We aimed to determine whether first morning void urine hormones in growing adolescents require adjustments and, if so, whether urinary creatinine or specific gravity are better adjustments. DESIGN AND METHODS: The study population was adolescents aged 10.1 to 14.3 years initially who provided fasting morning blood samples at 0 and 12 months (n = 343) and first morning urine every three months (n = 644). Unadjusted, creatinine and specific gravity-adjusted hormonal concentrations were compared by Deming regression and Bland-Altman analysis and grouped according to self-rated Tanner stage or chronological age. F-ratios for self-rated Tanner stages and age groups were used to compare unadjusted and adjusted hormonal changes in growing young adolescents. Correlations of paired serum and urinary hormonal concentration of unadjusted and creatinine and specific gravity-adjusted were also compared. RESULTS: Fasting first morning void hormone concentrations correlated well and were unbiased between unadjusted or adjusted by either creatinine or specific gravity. Urine creatinine concentration increases with Tanner stages, age and male gender whereas urine specific gravity was not influenced by Tanner stage, age or gender. Adjustment by creatinine or specific gravity of urinary luteinizing hormone, estradiol, testosterone, dihydrotestosterone and dehydroepiandrosterone concentrations did not improve correlation with paired serum concentrations. CONCLUSIONS: Urine steroid and luteinizing hormone concentrations in first morning void samples of adolescents are not significantly influenced by hydration status and may not require adjustments; however, if desired, both creatinine and specific gravity adjustments are equally suitable.

Measurement of testosterone by immunoassays and mass spectrometry in mouse serum, testicular, and ovarian extracts.

Accurate measurement of testosterone is important for reproductive endocrinology research, but the validity of direct (nonextraction) testosterone immunoassays, developed and validated for human serum, has not been appraised for application to mouse serum or steroidogenic tissue extracts. Testosterone was measured in serum and extracts of testis or ovary from male and female wild-type mice by 2 commercial direct testosterone immunoassays, with and without preassay extraction, and by the liquid chromatography, tandem mass spectrometry reference method. Results were compared hierarchically by correlation (Kendall's τ), regression (Passing-Bablok), and deviance (Bland-Altman) analysis, under the null hypothesis of perfect agreement between assays (slope = 1, intercept and deviation = 0). For mouse serum, immunoassays displayed an upward bias with performance better for male vs female sera and, within gender, improved by preassay extraction relative to liquid chromatography, tandem mass spectrometry. Testosterone was detectable in all serum samples, but few (male 54%, female 9%) were accurate (within 20% of the reference measurement). For mouse testis extracts, immunoassays were biased upwards, and preassay extraction improved immunoassay performance. Although testosterone was detectable in all extracts, a minority (45%) was accurate. For mouse ovary extracts, all correlations were poor with severe, upward bias, and while testosterone was detectable in all samples, virtually none were accurate. We conclude that these direct testosterone immunoassay kits provide relatively, but not absolutely, accurate results with male mouse serum and testis extracts but not with female mouse serum and ovary extracts, with performance improved by preassay extraction. Whether relative accuracy is fit for purpose depends on the experimental aims, design, and interpretation.

Pharmacokinetic-pharmacodynamic study of subcutaneous injection of depot nandrolone decanoate using dried blood spots sampling coupled with ultrapressure liquid chromatography tandem mass spectrometry assays.

CONTEXT: Testosterone (T) and nandrolone (N) esters require deep im injections by medical personnel but these often deposit injectate into sc fat so that more convenient sc self-administration may be feasible. OBJECTIVE: To investigate the feasibility and pharmacology of sc injection of N decanoate in healthy men using dried blood spot (DBS) for frequent blood sampling without clinic visits. SETTING AND DESIGN: Healthy male volunteers received 100 mg N decanoate by a single sc injection. Finger-prick capillary blood was spotted onto filter paper before injection daily at home for 21 d and stored at room temperature. Venous whole blood was also spotted onto filter paper before and weekly for 3 wk after injection. DBS were extracted for assay of N and T by liquid chromatography tandem mass spectrometry in a single batch with serum concentrations estimated with adjustment for capillary blood sample volume and hematocrit to define peak (N) or nadir (T) time and concentration from individual daily measurements. RESULTS: Daily serum N peaked 2.50 ± 0.25 (SEM) ng/mL at a median (range) of 6 (4-13) days causing a reduction in serum T from 3.50 ± 0.57 ng/mL at baseline to a nadir of 0.38 ± 0.13 (SEM) ng/mL (89 ± 3% suppression) at a median (range) of 8 (5-16) days. Simultaneously sampled capillary, venous whole blood, and serum gave almost identical results for serum T and N. Finger-pricks and sc injections were well tolerated. CONCLUSIONS: This study demonstrates that A) DBS sampling with liquid chromatography mass spectrometry steroid analysis achieves frequent time sampling in the community without requiring clinic visits, venesection, or frozen serum storage, and B) androgen esters in an oil vehicle can be delivered effectively by sc injection, thus avoiding the need for medically supervised deep-im injections.