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 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

Baseline CharacteristicsCharacteristic

Age (yr) 28.1 ± 11.5

Body weight (kg) 79.9 ± 7.5

BMI (kg/m2) 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

0

200

400

600

800

1000

1200

0 4 8 12 16 20 24

Serum Testosterone

Day 1-2

Day 9-10

Tes

tost

ero

ne (

ng/d

L)

Time (hrs)

Serum DHT

0

50

100

150

200

0 4 8 12 16 20 24

Serum DHT

Day 1-2

Day 9-10

DH

T (

ng/d

L)

Time (hrs)

Serum Estradiol

0

5

10

15

0 4 8 12 16 20 24

Serum Estradiol Day 1-2

Day 9-10

Est

radi

ol (

pg/

mL)

Time (hrs)

Serum SHBG

Free Testosterone

0

5

10

15

20

25

30

35

0 4 8 12 16 20 24

Free Testosterone

Day 1-2

Day 9-10

Fre

e T

est

oste

rone

(ng

/dL)

Time (hrs)

Maximal Hormonal LevelsDay 1-2 Day 9-10

Testosterone* (p=0.03) 1000 119 ng/dL 945 260 ng/dL

DHT* (p=0.01) 257 36 ng/dL 163 32 ng/dL

Free Testosterone (p= 0.77) 26.9 12.6 ng/dL 30.2 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?