Resident Research: Andrology topics Ada Lee, PGY2 Chief of Medicine Rounds 3/22/11

Projects I participated in CEP cell study NES-2 study Pharmacokinetics of modified release testosterone in healthy men

Pharmacokinetics of modified slow release oral testosterone in experimentally hypogonadal men. PI: John Amory MD, MPH

Background Hypogonadism affects 6-10% of men depending on age – Sx: low libido, fatigue, ED, osteoporosis, depression and poor physical performance (decreased muscle mass and strength) Testosterone can be repleted for either primary or secondary androgen deficiency – Current forms: alkylated testosterone, IM administration, testosterone patch, testosterone gels, buccal tablet – Limitations of many of the current forms of testosterone administration. Investigation: Oral testosterone Hypothesis: Administration of oral testosterone to healthy men who are rendered experimentally hypogonadal three times daily will increase and keep testosterone levels within the normal range

Methods Subjects: – Healthy men age – Exclusion: previous participation in drug study in the previous 6 months, lab abnormalities, testicular disease or trauma, psychiatric disorders, illicit drugs, >3 alcoholic beverages daily. – 14 subjects screened; 12 subjects recruited 1 excluded for HTN 1 excluded for PAD Acycline (300 mcg SQ x 1) Oral testosterone 300 mg PO TID WM Two 24 hour study periods – Day 1-2 and day 9-10 – Blood drawn at: 1, 2, 4, 6, 8,10, 12, 14, 16, and 24 hours after admission to the GCRC Testosterone DHT Estrogen SHBG

Baseline Characteristics Characteristic Age (yr)28.1 ± 11.5 Body weight (kg)79.9 ± 7.5 BMI (kg/m 2 )24.2 ± 1.5 FSH (IU/L)3.2 ± 1.5 LH (IU/L)5.4 ± 4.4 Testosterone (ng/ml)5.1 ± 1.3 PSA (ng/mL)0.91 ± 0.56

Serum Testosterone

Serum DHT

Serum Estradiol

Serum SHBG

Free Testosterone

Maximal Hormonal Levels Day 1-2Day 9-10 Testosterone* (p=0.03) 1000  119 ng/dL945  260 ng/dL DHT* (p=0.01) 257  36 ng/dL163  32 ng/dL Free Testosterone (p= 0.77) 26.9  12.6 ng/dL30.2  35.8 ng/dL ** **Outlier in the group where Free T was an order of magnitude greater than all other subjects

Adverse Events 8 non serious events in 6 subjects – 1 subject had symptoms of hypogonadism after the study period but before the follow up visit. – 1 subject had transient elevations of his AST, ALT and alkaline phosphatase in the setting of 6+ EtOH drinks which normalized despite continued administration of oral testosterone No GI side effects or intolerance

Discussion summary points Normalization of testosterone occurred within 1 hour of administration of testosterone with the majority of men maintaining hormone levels within the normal range DHT was elevated above the normal range but appeared to decrease over time Though total testosterone decreased at steady state, free testosterone levels remained the same correlating with an approximately 25% decreased level of SHBG

Conclusion Administration of oral testosterone at 300 mg three times daily appears to correct experimentally induced hypogonadism in healthy young men and may be a viable technique for future repletion of testosterone in androgen deficient men

Limitations Oral dosing of this medication was three times daily Does not mimic physiologic circadian rhythm of endogenous testosterone Though serum total testosterone and free testosterone are largely within normal limits, supraphysiologic levels of DHT were achieved Number of subjects was very small and data have large interindividual variability

Future directions Effect of meals and hormone absorption Monitoring hormone levels in larger populations particularly in light of the significant variability Significance of supraphysiological levels of DHT and relationship to prostate health

Acknowledgements Great thanks to: – UW Bill Bremner John Amory Stephanie Page Robert Bale Iris Neilson Mark Bentz Kathy Winter Kathryn Duncan Dorothy McGuiness Connie Pete – GSK Richard Clark Hui Zhi Mark Bush Ralph Caricofe

Thank You! Questions?