Resident Research: Andrology topics

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

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

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

4. 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

5. Methods • Subjects: • Healthy men age 18-55 • 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

6. Baseline Characteristics

7. Serum Testosterone

8. Serum DHT

9. Serum Estradiol

10. Serum SHBG

11. Free Testosterone

12. Maximal Hormonal Levels **Outlier in the group where Free T was an order of magnitude greater than all other subjects

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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 • HuiZhi • Mark Bush • Ralph Caricofe

19. Thank You! Questions?