1. Sex Hormones in Relation to Movement, Mood, and Cognition
Shalender Bhasin, MD
Professor of Medicine, Boston University School of Medicine
Chief, Section of Endocrinology, Diabetes, and Nutrition
Boston Medical Center Boston, MA

2. Testosterone’s Role in Evolutionary Selection of the Fittest
Strength
Visuospatial cognition
Territoriality
Aggression

3. Testosterone (nmol/L)C9
Longitudinal Changes in Serum T Levels: Baltimore Longitudinal Study of Aging 20 18
(177)
(144)
(151) 16
Testosterone (nmol/L)
(109) 14
(43)
(158) 12
Longitudinal effects of aging on date-adjusted testosterone. Linear segment plots for testosterone vs. age are shown for men with testosterone values on at least two visits. Each linear segment has a slope equal to the mean of the individual longitudinal slopes in each decade, and is centered on the median age, for each cohort of men from the second to the ninth decade. Numbers in parentheses represent the number of men in each cohort. Segments show significant downward progression at every age with no significant change in slopes for testosterone over the entire age range. 10 30 40 50 60 70 80 90
Age (Years)
Harman SM, et al. J Clin Endocrinol Metab. 2001;86:
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86:

4. Epidemiological Data: Weak Association of Low T and Outcomes
Directly weakly associated with:
Muscle mass (Baumgartner 1998; Melton 2000), strength (Morley 2000), and self-reported physical function (MMAS 2005)
Sexual desire (Beutel 2005)
BMD, vBMD and bone geometry (Khosla 2005)
Inversely associated with:
CAD (Wu 2003; von Eckardstein 2003)
Visceral fat (Seidell et al)
Mortality (Shore et al 2006)
Not associated with:
Aging-related symptoms (T’Sjoen 2004)
Prostate volume or LUTS (Schatzl 2000; Mohr 2007)
Erectile Dysfunction (Korenman, 1996 ; Morley 1997)
Depression indices (Seidman 2001; Barrett-Connor 2001; Schatzl 2000)

5. Testosterone and “Feelings”: Sexual Function in Older Men and Women

6. MMAS (Feldman et al, J Urol 1994); NHLHS (Laumann et al, JAMA 1999)
Epidemiology of Sexual Dysfunction in Middle-Aged and Older Americans: MMAS and NHLHS
25-30 million men in USA alone
52% of men, years of age, have some degree of ED
Incidence rates : 600, ,000 cases annually
MMAS (Feldman et al, J Urol 1994); NHLHS (Laumann et al, JAMA 1999)

7. Penile Erections Can Occur in the Absence of Testosterone
“But when the night was half-spent, he bethought him that he had forgotten in his palace somewhat which he should have brought with him, so he returned privily and entered his apartments, where he found the Queen, his wife, asleep on his own carpet bed embracing with both arms a eunuch of loathsome aspect and foul with grease and grime…So he drew his scimitar, and cutting the two in four pieces with a single blow, left them on the carpet….”
Sir Richard Burton, The Arabian Nights, 1850

8. Role of Testosterone in Spontaneous vs Induced Sexual Response
Compared to eugonadal men, hypogonadal men had:
Lower self-reported sexual activity, feelings and thoughts
Lesser number of spontaneous erections
Similar erectile response to visual erotic stimulus
Testosterone replacement for hypogonadal men:
Increased sexual feelings and thoughts, and sexual activity
Increased number of spontaneous erections
But did not change erectile response to visual erotic stimulus
Spontaneous, but not stimulus-induced, erections
are testosterone dependent
Testosterone stimulates sexual thoughts and feelings
Kwan et al, J Clin Endocrinol Metab 1983;57:557-62

9. T Improves Many Domains of Sexual Function in Androgen-Deficient Men
Spontaneous sexual thoughts and fantasies
(Kwan 1983, Bancroft 1985)
Frequency of spontaneous erections
(Kwan 1983, Cunningham 1990)
Overall sexual activity
(Wang 1996, 2004, Snyder 2000, Arver 1997)
Sexual arousal and enjoyment in response to erotic auditory stimulus
(Alexander 1997)
Frequency and duration of nocturnal erections
(Cunningham 1990, Carami 1990)

10. Meta-analyses of T Effects on Men with Sexual Dysfunction
Moderate treatment effect on libido in men with low T levels (0.4, 95% CI 0.05, 0.8)
Inconsistent effects on erectile function; small effect in men with T (<300 ng/dL)
No effect on orgasmic and ejaculatory function
Inconsistent effects on response to PDE5 inhibitors (Shabsigh 2004; Aversa 2003)
Caveats: imprecise estimates due to subject heterogeneity, variation in treatment regimens; incomplete reporting
Jain et al, 2001; Montori et al 2005

11. Androgen Deficiency and ED are Two Independently Distributed Disorders
Frequency of low bioavailable testosterone levels is similar in middle-aged and older men with ED and without ED (Korenman et al, JCEM 1990;71:963-70).
Six to 10% of men with ED have low testosterone levels (Buvat and Lemaire J Urol 1997;158:1764-9)

12. Testosterone Might be Necessary for Achieving Optimal Penile Rigidity
T restores penile NOS activity in castrated rats
(Seo 1999; Baba 2000, Penson 1996; Lugg 1996).
T enhances penile blood flow; essential for venous occlusion
(Mills et al, 1997, 1998).
T has trophic effects on cavernosal smooth muscle and bulbospongiosus and ischiocavernosus muscles.
(Shabsigh 2000)

13. Androgen Deficiency Erectile Dysfunction
Androgen Deficiency and ED are Two Independently Distributed Clinical Disorders
Androgen
Deficiency
Erectile
Dysfunction

14. COGNITIVE FUNCTION IN ELDERLY MEN WITH LOW T VS. NORMAL T
0.3
BVRT
CVLT-A
CVLT-D
ROT
TRAILS A
TRAILS B
0.2
0.1
Test Score (Z-Score)
Low T
Normal T
-0.1
-0.2
-0.3
p < .001
p < .01
p < .01
p < .001
p < .05
p < .05
-0.4
Moffat, et al, J Clin Endocrinol Metab 87:5001, 2002

15. Testosterone Trials and Cognition: A Meta-analysis
Some trials have shown improvements in verbal memory, verbal fluency, and visuo-spatial cognition (Cherrier et al, Janowsky et al)
Meta-analysis revealed no overall effect on a number of dimensions of cognition:
Imprecise results, suboptimal power, heterogeneity
Meta-analysis by Montori 2005 in Bhasin et al, JCEM 2005

16. T Dose Response in Young and Older Men: Change in Visual-Spatial Cognition
Scores
T Dose Effect P = NS
Age Effect P = NS
T Dose (mg)

17. Testosterone, Mood, and Depression
Higher prevalence of low T levels in men with clinical depression (Levitt et al, 1988; Seidman et al, 2002).
Testosterone replacement improves positive aspects of mood and decreases negative aspects of mood in healthy, hypogonadal men (Wang et al, 1996; Alexander et al, 1998) and HIV-infected men (Grinspoon et al, 2000; Rabkin et al, 2000).
Subjects with refractory depression receiving T had greater improvements in Hamilton Depression score than those on placebo (Pope 2003).

18. Testosterone Effects on Physical Function and Mobility

19. Change in Fat Free Mass (Kg)
Effects of A Supraphysiologic Dose of Testosterone on Fat–Free Mass in Healthy Men
6 -
4 -
2 -
0 -
Placebo Testosterone Placebo Testosterone
No Exercise Exercise
Change in Fat Free Mass (Kg)
0.8± ± ± ±0.6
Bhasin S, Storer TW, et al, N Engl J Med 1996 19

20. Evidence of Testosterone’s Anabolic Effects
T replacement of hypogonadal men increases
FFM (2.3 kg, CI 1.2, 4.0)
muscle size, and
muscle strength (Bhasin 1997; Wang 2000; Snyder 2000)
T supplementation of HIV-infected men with weight loss increases:
body weight (1.5 kg, 0.03, 3.1)
LBM (1.3 kg, CI 0.2, 2.2)
muscle strength, and
some domains of HRQOL (Bhasin 1998, 2000; Grinspoon 1998, 2000)

21. Meta-analysis Plot of Lean Body Mass Change in Older Men
T increases muscle mass
Mean Difference in LBM (kg) Change between Placebo and T Groups
Bhasin Nature CPEM 2005

22. T Dose Response in Young and Older Men: Change in Fat Free Mass
T Dose Effect P <0.0001
Age Effect P = 0.22
Change in T X age P = 0.46
Change in
FFM (kg)
T Dose (mg)
Bhasin et al JCEM 2005

23. T Dose Response in Young and Older Men: Change in Leg Press Strength
T Dose Effect P = 0.008
Age Effect 0.84
Age X Change in serum T 0.29
Change in
Leg Press
Strength (lb)
T Dose (mg)
Bhasin et al JCEM 2005

24. T Effects on Physical Function
Meta-analysis:
No significant effect on overall SF-36 HRQOL score
Significantly greater improvement in physical function domain than placebo (0.5,95%CI 03, 0.9)
Montori in: Bhasin et al, JCEM 2006 in press
Snyder et al JCEM 1999

25. Possible Reasons for Failure to Demonstrate Consistent Improvements in Measures of Physical Function
Inclusion of men who were not clearly hypogonadal
T dose and conc. relatively low
Studies performed in healthy older men, not in frail or impaired men
Problems with measurements of muscle performance and physical function:
Are older men relatively insensitive to the anabolic effects of androgens?

26. Testosterone Supplementation: Long-term Monitoring Concerns
Erythrocytosis
Prostate cancer and exacerbation of BPH
Cardiovascular disease
Fluid retention
Gynecomastia
Sleep apnea
When a patient is started on T supplementation, treatment is generally for life. The physician's responsibility for his monitoring is also for life. The areas requiring special attention are:
The prostate. Evidence indicates that T administration to hypogonadal men produces negligible to modest increases in prostate size and prostatic specific antigen. However patients with significant obstructive symptoms or with suspected or documented cancer of the prostate (or breast) constitute absolute contraindications for T administration.
Lipid profile. Evidence is emerging supporting the concept that low levels of T are associated with potentially unfavorable changes in triglycerides and HDL-C and that such abnormalities can be corrected by restoring physiological levels of androgens. Therefore, careful follow-up of the lipid profile is advisable when supplementing androgens in patients with significant risk factors for cardiovascular disease.
Sleep apnea may be exacerbated by T administration. The same applies to polycythemia. Therefore, T must be administered to these patients with caution.
Reports of liver toxicity manifested by jaundice and alteration of liver function studies have been limited almost exclusively to the methylated forms of testosterone. The injectable and oral esters of T as well as the transdermal are largely free of this adverse effect. Nevertheless, yearly liver function tests following institution of androgen therapy are advisable.
The effect of T supplementation on a patient’s mind and emotional state should also be evaluated.
Morales A. Int J Impot Res. 2000;12(suppl):10. Abstract S11.
Heaton JP et al. In: Male Sexual Function. Humana Press; 2001:
Morales A. Int J Impot Res. 2000;12(suppl):10. Abstract S11.
Andropause Consensus Panel 2001; Bhasin S, J Androl 2001;22(5):718-31; Bhasin et al J Androl 2003

27. Testosterone Supplementation and Risk of Prostate Cancer: Issues
Many older men have microscopic foci of prostate cancer; T might make these subclinical foci grow.
Older men with low T levels may have prostate cancer (Morgentaler et al, 1996)
PSA levels increase after T administration (Meikle et al, 1997; Behre et al, 1994; Cooper et al, 1994).
Inherent bias towards detection of greater number of prostate events in T-treated men (Calof 2005)
Androgen therapy is normally for life; monitoring, therefore, is a serious commitment for both physician and patient. Monitoring should occur quarterly for the first year—and yearly thereafter—if no adverse events are detected.
In men with ED, positive changes should be evident within 3 months after onset of treatment. If no improvement has occurred, comorbidities should be investigated.
Tremblay J, Morales A. Aging Male. 1998;1:
Adapted from Bhasin S, J Androl.2001;22: Bhasin et al, J Androl 2003

28. Meta-Analysis of Adverse Events in Testosterone Replacement Trials in Older Men
Rate for
testosterone
Rate for placebo
Odds Ratio
95% CI
Prostate cancer
5/643
2/427
1.11
0.48, 2.58
PSA>4
27/643
14/427
1.20
0.68, 2.12
Biopsies
21/643
1/427
1.93
0.86, 4.37
Total prostate events (cancer, biopsies, PSA>4, increased IPSS score)
56/643
18/427
1.80
1.08, 3.00
Hct>50%
35/643
3.69
1.20, 3.28
All cardiac events (A fib, MI, chest pain, CABG, CVA)
15/643
1.10
0.55, 2.21
Death
0/643
0.79
0.31, 1.98
*computed using the Clopper-Pearson method ; random effects model

29. Testosterone and Cardiovascular Risk
Testosterone levels are lower in men with CAD than in healthy controls (Alexanderson 1996)
Physiologic T replacement has little or no effect on plasma HDLC in older men (Snyder et al, 1999; Tenover 2000; Sih et al, 1997)
Testosterone
improves coronary blood flow (Ong et al, 2000; English et al, 2000)
Reduces visceral fat and improves insulin sensitivity in middle aged men (Marin et al 1992)
Retards atherosclerosis progression in LDL-receptor deficient mice (Nathan et al, 2001)
T supplementation induces increase in LV mass (Casaburi unpublished)

30. Sophie’s Choice
Trade-off between beneficial effects of testosterone and the uncertainty about their adverse effects
Hypothesis:
SARMs and signaling effectors downstream of AR would provide better risk : benefit ratio

31. Mechanisms of Androgen Action: Targets for Drug Discovery

32. Mechanisms of Androgen Action: Testosterone Induces Muscle Fiber Hypertrophy
2000 *
600 vs 25mg: P<.05
1500
600 vs 50 mg: P<.05
Change in Type II
Fiber Area (mm2)
600 vs 125 mg: P<.05
300 vs 25 mg: P<.05 *
1000
500
P = 0.003 *
1800
600 vs 25 mg: P<.05
600 vs 125 mg: P<.05
1400
300 vs 25 mg: P<.05
Change in Type I
Fiber Area (mm2) *
1000
600
200
P = 0.003
TE Dose mg/wk
Sinha-Hikim et al, AJP Endo Metab 2002

33. Testosterone Increases Myonuclear and Satellite Cell Number
Number / mm 4 8 12 16
125 mg mg mg
Satellite Cell
Testosterone Enanthate Dose Levels * **
P = 0.04
P = 0.03
SInha-Hikim et al, AJP 2003

34. DHT Dose-Dependently Stimulates Myogenic Differentiation of Mesenchymal Pluripotent Cells
w/o 1st ab
-DHT
0.3 nM
Immunocytochemistry
1 nM
3 nM
30 nM
***
***
***
Image Analysis **
Singh et al, Endocrinology 2003

35. A Model for Androgen Action on the Muscle
Pluripotent Stem Cells
A Model for Androgen Action on the Muscle
Pre-adipocyte progenitor cell
Mature Adipocyte
Myoblast
Myotube
Satellite cell
Fat cell lineage
Muscle cell lineage
MyoD
MHC
Desmin
Pre-adipocyte + -
Mesenchymal Stem Cells
LPL
PPARγ
C/EBPα
Bhasin et al, J Gerontol Med Sci 2003; Bhasin et al Nature CPEM 2005

36. Wnt Signalling Pathway
Extracellular
Wnt
Frizzled
Cytoplasm
LiCl
LRP-5/6 AR
Dsh
Integrin-linked kinases AR
GSK-3
APC
β-catenin
Axin
β-catenin
β-catenin
β-catenin
Nucleus
TCF-4/LEF
BJS-1
Target genes
Myogenesis
Cell Fate
Adipogenesis

37. Alterations in Intramuscular Gene Expression Associated with T Administration in HIV-Infected Men with Weight Loss
PRKAA2, PRKWNK1:
AMPK, insulin signaling
DIPA: adipogenesis inhibitor
RORA: nuclear hormone
Receptor: interaction
with MyoD
NCOA3: hormone rec.
coactivator, IGF signaling
histone acetyltransferase,
interacts with p300/CBP
SYNCRIP: p68 kinase
Insulin signaling
IL6ST: gp130 cytokine
Receptor / STAT
SHARP:
androgen receptor, Notch signaling
TCF8: suppresses IL2
IGF1: Insulin-like
growth factor 1
Placebo Testo
TNFSF10:
TRAIL / Apoptosis
NFAT5: transcription
factor, WNT signaling
TCF4: beta-catenin binding
transcription factor,
Wnt signaling
AR: androgen receptor
SOS2: MAPK
signaling
SOS1: MAPK signaling
Placebo Testo
ATRX: helicase,
chromatin remodelling
TNFAIP6:
hyaluronan-binding,
TNF inducible
TK2: mitochondrial dNTP kinase
muscle activity
DMPK: dystrophia myotonica
protein kinase
MADH5: SMAD5, TGFb signaling
APOBEC3C: RNA editing
Affymetrix U133A 2.0 chip
Montano et al 2006

38. Anti-BJS-1 Antibody Blocks T Effects on Myogenic Differentiation
T+Anti-BJS-1
BJS-1
T+BJS1-Ab
BJS-1
T+Anti-BJS-1
BJS-1
Singh et al (unpublished)
T+BSJ1-Ab
BJS-1

39. Jasuja, Singh, Bhasin (unpublished)
BJS-1 as an Example of T-Activated Target that Acts Downstream of AR, Promotes Muscle Mass and BMD, but Spares the Prostate
Fat-Free Mass
Bone Mineral Density
BJS-1
Jasuja, Singh, Bhasin (unpublished)

40. SARM Discovery Based on Recognition of Conformational Change
Concern about prostatic effects in older men a major hurdle to the use of androgens as anabolic drugs
Current screening strategies are based on AR binding and transactivation assays and favor selection of partial agonists: a flawed strategy
Hypothesis: Three classes of ligands - androgen agonists, antagonists, and SARMs - confer distinct conformations to the androgen receptor protein upon binding to its ligand binding domain (LBD).

41. DHT-induced Changes in Emission SpectraAR
lex = 278 nM
(Tyrosines)
lex = 290 nM
(Tryptophans)
AR + DHT AR
AR + DHT

42. Tryptophan fluorescence spectra for AR LBD as a function of guanidinium hydrochloride concentration
When G-HCl concentrations were varied tryptophan emission intensity varied in the presence of the three classes of ligands.

43. Jasuja and Bhasin unpublished
A High Throughput Screening Strategy Based on Conformational Change and FRET for SARM Development
Jasuja and Bhasin unpublished

44. Conclusions
Total and free T levels decline with advancing age and are weakly associated with clinical outcomes.
Strong evidence that T supplementation increases:
skeletal muscle mass
maximal voluntary strength and leg power
decreases whole body and regional fat mass
libido
Weak evidence that
T therapy improves physical function, mood, and erectile function
Effects of T on clinical outcomes in older men with specific clinical syndromes: unknown
The long term risks: unknown

45. Institute of Medicine Expert Panel Report on the Future of Testosterone Research
Short-term RCTs of no longer than 1-year duration
Older men with specific syndromes, attributable to androgen deficiency, and low T levels
Replacement doses of testosterone
Adequately powered to determine efficacy using clinically relevant outcomes, rather than surrogate endpoints
Conduct larger trials to determine safety only if efficacy has been demonstrated
Blazer et al, 2003; Snyder 2004; Barrett-Connor and Bhasin 2004

46. Mechanisms of Androgen Action
Androgens modulate differentiation of mesenchymal multipotent stem cells
Androgens regulate mesenchymal stem cell differentiation by promoting the association of AR with beta-catonin and activating TCF-4.
Speculation
Mechanism-specific high throughput screening strategies based on recognition of unique conformational change provide powerful tools for discovery of SARMs that have the desired tissue-selectivity

47. Thank you to my partners:
Exercise Physiology
Tom Storer
Nathan LeBrasseur
Linda Woodhouse
Histomorphology
Indrani Sinha-Hikim
Mechanisms
Rajan Singh
Monty Montano
Jorge Artaza
Ravi Jasuja
Nestor Gonzalez-Cadavid
Morris
Res Coordinators
Connie Dzekov
Jeanne Dzekov
Rachelle Bross
Marjan Javanbakht
hMSCs
Ravi Jasuja
Clinical Investigators
Atam Singh
Olga Calof
Helen Choi
Behavioral Studies
Peter Gray
Ray Tricker
Cardiovascular Markers
Chris Roberts
Conformational Studies
Collaborators
Richard Casaburi
Kevin Yarasheski
Fred Sattler
James Kirkland
Stefan Arver
Harrison Pope
Grant Support
NIA, NIDDK, NICHD

48. King Testosterone OH O

49. Jasuja and Bhasin unpublished
Conceptual Framework and Feasibility of a High Throughput Screening Strategy for SARMs
Jasuja and Bhasin unpublished

50. Lesson 3 for Drug Discovery
Mechanism-specific high throughput screening strategies based on recognition of unique conformational change provide powerful tools for discovery of SARMs that have the desired tissue-selectivity

51. Barriers for Regulatory Approval
T increases muscle mass and strength in older men, but improvements in physical function and clinical outcomes not demonstrated in men with physical dysfunction
Uncertainties
How to operationalize the concept of individuals at risk for physical dysfunction and disability?
What outcomes should be used as measures of efficacy in clinical trials?

52. Mechanisms of Androgen Action
Mechanism-specific high throughput screening strategies based on recognition of unique conformational change provide powerful tools for discovery of SARMs that have the desired tissue-selectivity

53. Lesson 2 for Drug Discovery: Wnt-Target Genes, such as BJS-1, are Attractive Candidates
Wnt signaling pathway:
a major determinant of mesenchymal stem cell differentiation
β-catenin at the crossroads of several signaling pathways: targets downstream would have greater specificity
Pharmacophores that activate Wnt signaling would promote myogenesis and inhibit adipogenesis.
Pharmacophores such as BJS-1 that activate Wnt-target genes downstream of AR would selectively increase muscle mass without affecting the prostate.

54. Testosterone Supplementation in Men with Refractory Depression
Study Design: Placebo-controlled, randomized, single-center, trial
Patients: 23 men with refractory depression on anti-depressant therapy, with serum T <350 ng/dL.
Treatment: Placebo or 10 g T gel daily X 8-weeks
Results: Subjects receiving T had greater improvements in Hamilton Depression score (-7.3) than those on placebo (-0.3).
Pope et al, Am J Psych 2003;160:

55. Endocrine Society Expert Panel’s Guidelines for Monitoring During Androgen Therapy
At baseline, at 3, 6, 12 months after starting T therapy, monitor hemoglobin, PSA, DRE, AUA symptom score, sleep apnea scores
Obtain Urological consultation if:
Change in PSA of >1.4 ng/ml in any one year period (Finasteride Study group, Gormley, 1992)
PSA velocity of >0.40 ng/ml/year (Carter et al, 1995).
Bhasin S, J Androl 2001;22:718-31; Bhasin et al, 2003; Endocrine Society 2005

56. An Investigator’s Prayer
Oh Great Spirit:
Bless my partners (Tom Storer, Rajan Singh, Ravi Jasuja, Indrani-Sinha-Hikim, Linda Woodhouse, Jeanne and Connie Dzekov, Rich Casaburi, Jorge Artaza, Nestor Gonzalez-Cadavid, Kevin Yarasheski) for generating the data that make me look smarter than I am.
Please, soften the hearts of the reviewers of our grants and manuscripts, and keep us funded!

57. The US Endocrine Society Expert Panel’s Recommendations: 2005
Recommended against a general clinical policy of offering testosterone therapy to all older men with low testosterone levels. (1|).
Suggested that clinicians consider T therapy on an individualized basis to older men with consistently low T levels and significant symptoms of androgen deficiency, after discussion of the risks and benefits (2|)
Suggested clinicians offer T therapy to men with low T levels and low libido and/or erectile dysfunction in order to improve libido (2|) and erectile function (2|).

58. CHANGE IN 6-MINUTE WALKING DISTANCE IN 6 MONTHS
TESTOSTERONE TRIAL
CHANGE IN 6-MINUTE WALKING DISTANCE IN 6 MONTHS *+
Meters *
*p<.05 vs control;
+ p<.05 RT+T vs RT
Testosterone treatment improved 6-minute walking distance to a greater extent than placebo in older men approaching frailty.

59. Evidence that Androgen Binding Induces Specific Conformational Change
2nd order derivative spectra follows the bears and lambert’s law; the DHT induced
perturbations in tyrosine and tryptophan residues can be calculated as below: a b

60. Calof and Bhasin J Gerontol 2005
Inherent Bias Towards Overestimation of Prostate Events in Testosterone-Arms of Clinical Trials
Prostate biopsies usually triggered by PSA increments in clinical trials
PSA increments are more likely in T-treated men than in placebo-treated men.
Therefore, T-treated men likely to undergo greater number of prostate biopsies, resulting in detection of a greater number of subclinical prostate cancers.
Calof and Bhasin J Gerontol 2005

61. Are Older Men Less Sensitive to the Anabolic Effects of Androgens?

62. T Regulates Many Domains of Sexual Function in Men
T replacement of hypogonadal men increases:
Spontaneous sexual thoughts and fantasies (Kwan 1983, Bancroft 1985)
Frequency of spontaneous erections (Kwan 1983, Cunningham 1990)
Overall sexual activity (Wang 1996, 2004, Snyder 2000, Arver 1997)
Sexual arousal and enjoyment in response to erotic auditory stimulus (Alexander 1997)
Attentiveness to erotic stimulus (Alexander 1997)
Frequency and duration of nocturnal erections (Cunningham 1990, Carami 1990)
T does not affect response to VES (Davidson 1978; Kwan 1979)

63. The Role of Testosterone in Penile Erections
“But when the night was half-spent, he bethought him that he had forgotten in his palace somewhat which he should have brought with him, so he returned privily and entered his apartments, where he found the Queen, his wife, asleep on his own carpet bed embracing with both arms a eunuch of loathsome aspect and foul with grease and grime…So he drew his scimitar, and cutting the two in four pieces with a single blow, left them on the carpet….”
Sir Richard Burton, The Arabian Nights, 1850

64. Team Testosterone Exercise Physiology Stable Isotope Work Lipids
Tom Storer
Linda Woodhouse
Stable Isotope Work
Kevin Yarashesji
Lipids
Petar Alaupovic
Insulin Sensitivity
Tom Buchanan
Stan Hsia
Co-investigators
Rich Casaburi
Mitch Harman
Keith Beck
Clinical Investigators
Shalender Bhasin
Norm Mazer
Philip Knapp
Andrea Coviello
Atam B. Singh
Olga Calof
Fellows
-MaClara Padero
-Ricky Mac
-Helen Choi
Mechanisms
Rajan Singh
Ravi Jasuja
Jorge Artaza
Nestor Gonzalez-Cadavid
John Flanagan
Carl Morris

65. Team Testosterone Clinical Research Team Director: Linda Woodhouse
Research Coordinators:
-Tina Davidson
-Connie Dzekov
-Jeannie Dzekov
-Veronica Sanatana
-Jeff Celzada
Exercise Physiology Laboratory
Director: Thomas W. Storer
Tech: Lynn Magliano
Body Composition
Linda Woodhouse
Thomas W. Storer
Hormone Assays
Indrani Sinha-Hikim
Mag Que

66. Is Testosterone the Fountain of Youth?

67. Myocardial O2 Supply/Demand
Hagl, Bas Res Cardiol 1977;72:344
Spahn, J Thor Card Surg 1993;165:694
Anesth Analg 1995;80:219
Maximum O2 extraction
Maximum coronary vasodilation O2
ml/min
60% occlusion
CHF
CHF
80% occlusion
ischemia
ischemia
Burch GE, Dis Chest 1965;48:225-32

68. Dose-Selection: Trade-Off Between Adverse Effects and Beneficial Effects
Very substantial skeletal muscle remodeling is possible in healthy, older men with androgen administration.
Trade-off between the dose, anabolic effects and adverse events
Best trade-off was achieved at 125 mg/week TE dose:
Very low frequency of AEs
Serum T levels in the high normal range
Average 4.2 kg increase in FFM
Average 28 kg gain leg press strength
SARMs that are preferentially anabolic but do not have the adverse effects of T would be useful in sarcopenia associated with aging and chronic illness.

69. Wnt Signalling Pathway
Extracellular
Wnt
Frizzled
Cytoplasm
LiCl
LRP-5/6 AR
Dsh
Integrin-linked kinases AR
GSK-3
APC
β-catenin
Axin
β-catenin
β-catenin
β-catenin
Nucleus
TCF-4/LEF
Target genes
Myogenesis
Cell Fate
Adipogenesis

70. Role of 5-Alpha Reductase and Aromatase in Mediating Androgen Action on Muscle
-Very low levels of 5-alpha reductase activity in muscle (Bartsch et al, 1980)
-Patients with 5-alpha reductase mutations have normal muscle development at puberty (Imperato-McGinley et al, 1976)
-Finasteride-treated men do not undergo muscle loss
Aromatase
-Aromatase KO mice have decreased muscle mass and increased fat mass (Fisher et al, 1998)

71. T Dose-dependently Improves Overall Sexual Function Scores in Older Men
Change in Overall Sexual Function
Testosterone Dose (mg/week)
Overall ANOVA P=0.003.
Gray et al 2005 in press

72. T Dose Response in Young and Older Men: Change in Hemoglobin
T Dose Effect P <0.0001
Age Effect P < 0.001
Change in
Hemoglobin
(g/L)
T Dose (mg)

73. Effect of T Replacement on LV and RV Mass in Men with COPD
LEFT VENTRICULAR
MASS
RIGHT VENTRICULAR
MASS
Exercise – + – + – + – +
TE – – + + – – + +

74. Change in Specific Tension
No Exercise
Exercise
Placebo
Testosterone
Placebo
Testosterone *† *†
Percent Change from Baseline
overall ANOVA, p=0.001
* p<0.001 vs Placebo, No Exercise
† p<0.001 vs Testosterone, No Exercise

75. Changes in Erectile Function
Change in Waking Erections
Change in Spontaneous Erections
Testosterone Dose (mg/week)
Testosterone Dose (mg/week)
Overall ANOVA P=0.024
Overall ANOVA P=0.380

76. T Dose Response in Young and Older Men: Change in Plasma HDL Cholesterol
(mg/dL)
T Dose Effect P = 0.001
Age Effect P = 0.67
Change in T level X Age effect P = 0.86
T Dose (mg)

77. Mechanisms of Androgen Action: Testosterone Induces Muscle Fiber Hypertrophy
2000 *
600 vs 25mg: P<.05
1500
600 vs 50 mg: P<.05
Change in Type II
Fiber Area (mm2)
600 vs 125 mg: P<.05
300 vs 25 mg: P<.05 *
1000
500
P = 0.003 *
1800
600 vs 25 mg: P<.05
600 vs 125 mg: P<.05
1400
300 vs 25 mg: P<.05
Change in Type I
Fiber Area (mm2) *
1000
600
200
P = 0.003
TE Dose mg/wk
Sinha-Hikim et al, AJP Endo Metab 2002

78. Sinha-Hikim et al, AJP Endo 2003
Changes in Myonuclear and Satellite Cell Number After Treatment with GnRH Agonist and Testosterone 16 * 12
Myonuclear
Number / mm 8
P = 0.04 ** 4 8 *
P = 0.03
Satellite Cell
Number / mm 4
125 mg mg mg
Sinha-Hikim et al, AJP Endo 2003
Testosterone Enanthate Dose Levels

79. DHT Dose-Dependently Stimulates Myogenic Differentiation of Mesenchymal Pluripotent Cells
w/o 1st ab
-DHT
0.3 nM
Immunocytochemistry
1 nM
3 nM
30 nM
***
***
***
Image Analysis **
Singh et al, Endocrinology 2003

80. Stimulation of MyoD Expression in 10T1/2 cell by T and DHT is inhibited by Bicalutamide
DHT (10nM)
Blank
T (30nM)
control
DHT (10nM) + Bic (100nM)
T (30nM) + Bic (300nM)
400X
Immunocytochemistry ** 30 * 20
Pos Nuclei/Total Nuclei x 100
C vs. DHT p<0.01
C vs. T p<0.05
DHT vs. DHT + Bic p<0.001
T vs. T + Bic p<0.001
Image Analysis
###
### 10
Singh et al, 2003 C
DHT T
DHT+ Bic
T + Bic

81. Dose-Dependent Inhibition of Adipogenesis by Androgens in Mesenchymal Pluripotent Cells
Fat cells /10 fields
Singh et al, 2003

82. DHT Inhibits the Expression of PPAR-gamma and C/EBP-alpha in C3H10T1/2 Cells
: DHT (nM)
PPAR- -
52 kD
42 kD
C/EBP
30 kD
GAPDH -
40 kD
Singh et al, Endocrinology 2003

83. A Dominant Negative TCF4 cDNA Construct Blocks Testosterone Effects on Myogenesis in Mesenchymal Pluripotent Cells
MHC+ Myotubes/hpf

84. Effect of T Supplementation on Bone Mineral Density in Older Men
Study Duration T Dose Results
Tenover 3 years 150-mg TE/2 wks Incr spinal and
fem BMD
Snyder 3 years 6-mg scrotal ptach Incr. spinal BMD
Kenny 1 year Nongenital patch Incr. Femoral BMD

85. Summary and Conclusions
T supplementation in eugonadal men, older men and men with chronic diseases and low T levels increases:
skeletal muscle mass
maximal voluntary strength and leg power
decreases whole body and regional fat mass
T effects on physical function and health-related outcomes (disability, falls, well-being, QOL): unknown
Uncertainties:
The long term risks: unknown
No consensus on how to operationalize the concept of individuals at risk for disability
Do women have different T dose response relationships?

86. Mechanisms of Androgen Action
Androgen increase muscle mass and reduce fat mass by promoting differentiation of mesenchymal pluripotent stem cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage.
Androgens regulate mesenchymal stem cell commitment by activating Wnt signaling.
Speculation
Models that incorporate H:R binding, AR conformational change, thermodynamics, DNA binding, and in vitro myogenic activity would provide a more precise prediction of SARM activity.
SARMs hold great promise for treatment of sarcopenia associated with aging and chronic illness, and for fat accumulation syndromes.

87. Adverse Events Associated with T Administration in Older Men: A Meta-Analysis
Criteria for inclusion in the systemic review:
Placebo-controlled, RCT
Middle-aged or older men (>45 years of age)
Medically stable individuals free of specific diseases
“Replacement” doses of testosterone or its esters
Number of studies included = 17
Number of subjects in placebo group = 427
Number of subjects in T group = 643

88. Operationalizing the Concept of Individuals at Risk for Disability
Fried’s multi-dimensional construct of frailty (2001)
Predicts risk of falls, disability, and mortality
Affects only 7% of men and women >65
Difficult to operationalize in clinical trials
Identifies a group with high morbidity and mortality
Gill: Battery of physical function measures (1998, 1999)
Guralnik: lower extremity function (1994, 1995)
Sarcopenia defined in terms of appendicular skeletal muscle mass (Melton 2000; Baumgartner 1998)

89. Sarcopenia as an Excellent Biomarker of Aging
Is predictive of clinical outcomes: falls, fractures, and disability (Melton 2001; Baumgartner 1998)
In cross-species comparisons, sarcopenia is predictive of biological age and mortality (Herndon 2002; Guarente 2000)
Responsive to anabolic interventions (Bhasin 2001; Snyder 1999; Tenover 1992, 2000; Roubenoff 2002)
Can be measured precisely and accurately (Kim et al, 2002; Heymsfield 1998)
Significant changes demonstrable over short durations

90. What Outcomes Should be Measured in Clinical Trails of Anabolic Therapies?
Measures of muscle mass (DEXA, D2O)
Measures of muscle performance
Muscle strength, power, and fatigability
Measures of Physical Function
Health-related outcomes
Sense of well-being
Energy/fatigue
Affectivity balance
Physical activity
Disability scale

91. Summary and Conclusions
Different androgen-responsive functions have different T dose-response relationships
Anabolic effects of T are correlated with T dose and conc.
Older men are NOT less sensitive to anabolic effects of T.
Older men differ from young men in other aspects:
Older men have higher serum T levels: decreased clearance
Older men have higher frequency of Hct> 54%, edema, and prostate events
Older men had a greater increase in Hg/Hct

92. Edema and CHF During Testosterone Administration
Leg edema observed largely in older men receiving supraphysiological doses
Occurred within 1-4 weeks of starting treatment
Was associated with SOB in two men who developed leg edema; echocardiograms in these two men revealed normal ejection fractions and evidence of diastolic dysfunction
Pre-existing heart disease?

93. We have learned much, but much remains unknown…
T supplementation of older men with low T levels increases FFM, muscle size, and strength, but we do not know whether it can induce meaningful gains in physical function, risk of disability, sense of well being, HRQOL.
Long term safety unknown
Uncertainty about how to operationalize the concept of individuals at risk for disability
Do women have different dose-response relationships than men?

94. We have learned much, but much remains unknown…
Mechanisms
How do androgens increase muscle mass?
Are anabolic effects AR-mediated? Non-genomic effects
The kinetics and thermodynamics of T:AR interaction
The role of 5-alpha reduction and aromatization

95. Effects of Testosterone and Resistance Exercise on Lean Body Mass (DEXA) in HIV+ Men with Low T Levels
No Exercise
Exercise * *
Change in FFM (kg)
Placebo
Testosterone
Placebo +
Exercise
Testosterone +
Exercise
* p<0.005 vs zero change
Bhasin et al, JAMA 2000

96. Androgen Therapy: Contraindications
Prostate cancer
Breast cancer
BPH with severe symptom score or bladder outlet obstruction
Erythrocytosis with hematocrit >52%
Severe sleep apnea
Severe (class IV) congestive heart failure
Older men are the most likely candidates for androgen therapy. The choice of testosterone preparation depends on several factors, including availability, cost, and tolerance.
A clear indication implies that symptoms of ADAM are present. It should be remembered that androgen deficiency affects different organs/systems with variable degrees of severity. Biochemical confirmation of hypogonadism is desirable prior to onset of therapy.
Prostate safety remains the primary concern with androgen therapy. The presence of prostate cancer must be ruled out prior to testosterone administration. Breast cancer is also a contraindication.
The presence of severe bladder outlet obstruction (BOO) is an absolute contraindicate for testosterone supplementation; moderate obstructive symptoms are not.
Tremblay J, Morales A. Aging Male. 1998;1:
Morales A et al. Int J Impot Res. 1996;8:95-97.
Adapted from Bhasin, S, J Androl 2001;22:718-31; Andropause Consensus Panel, 2001
Tremblay J, Morales A. Aging Male. 1998;1:

97. Issues in SARM Development
Can androgen administration improve muscle performance and produce meaningful improvements in health-related outcomes?
What patient populations provide the best opportunities for initial efficacy trials?
Uncertainty about measures of muscle performance and physical function that can be used as outcome measures in efficacy trials
Lack of good correlation between Kd and in vivo potency
Better measures of hormone:receptor interaction
Lack of good in vitro bioassays that are predictors of in vivo anabolic efficacy
Lack of good animal models of sarcopenia that can be used to demonstrate beneficial effects of SARMs

98. T Dose Response in Young and Older Men: Change in Young’s Mania Rating Score
T Dose (mg)

99. Are Older Men Relatively Insensitive to Androgen Effects?
Many changes during the aging process such as decreased sexual function, osteoporosis, and muscle loss are similar to those associated with androgen deficiency.
Total and free T conc. in older men are lower than younger men, but most healthy older men have serum T in eugonadal range.

100. Hypotheses-2
Older men are not insensitive to the anabolic effects of T on lean body mass, muscle size and strength.

101. Compliance with Study Treatment
Young Men:
Only one man in 126 mg dose missed one TE injection
GnRH agonist: 100%
Older Men
TE: 100%

102. Study Design Sample Size: 11-13 men in each of the 5 treatment groups
Treatment Duration: 20 weeks
Exercise stimulus was controlled.
Protein and energy intake
35 Kcal/kg/day, 1.5 g protein/kg/day
Compliance verified by 3-day food records and 24-hr phone recall

103. T Dose Response in Young and Older Men: Change in Sexual Activity & Desire
Scores
T Dose Effect P = NS
Age Effect P = NS
T Dose (mg)

104. T Dose Response in Young and Older Men: Change in PSA
(ng/ml)
T Dose Effect P = 0.58
Age Effect P = 0.65
Change in T level X Age Effect P = 0.13
T Dose (mg)

105. Testosterone Effects on HRQOL: Rationale
Lean body mass is an important determinant of HRQOL in HIV-infected individuals (Wilson et al, 1999)
Testosterone improves LBM and HRQOL in HIV-infected men (Grinspoon et al, 1998)
Aging-associated impairment of physical function is associated with significant decrease in overall HRQOL (Wier et al).
TRT improves rehabilitation outcomes in ill, older men (Bakhshi et al, 2000).

106. T Dose Response in Young and Older Men: Change in Free T
T dose effect, P<0.0001
Age effect, P<0.0001
Change in Free T (pg/mL) 25 50
125
300
600
TE (mg)

107. Prevalent Dogma: Protein Synthesis as the Target of Androgen Action
This hypothesis does NOT explain:
The reciprocal decrease in fat mass
The observed increase in myonuclear and satellite cell number
AR localization localization in precursor cells mostly outside the muscle fiber
Pluripotent Stem Cell Differentiation as the Target of Androgen Action: An Alternative Hypothesis
Bhasin et al, J Gerontol 2003

108. Effect of Age in Men on Body Fat, Lean Body Mass, and Weight 80 70 60 50 40 30 20 10
Age (years)
Body Composition Component (kg)
Forbes GB, Reina JC, Metab 1970;19:653

109. Androgen Receptor is Expressed in Satellite Cells
CD34 AR
CD34+AR
AR Immunostaining

110. Androgens Upregulate MyoD and MHC Expression**
***
mRNA *
Myo D mRNA by Real-Time PCR
MHCII Protein by Western
T (nM)
-Az
215 kDa
MHCII
GAPDH-
40 kDa

111. Forest Plot of Mean Difference for Fat Mass Change
-4.0
-2.0
0.0
2.0
4.0
Mean Difference
Study
Grinsp 2000
Bhasin 1998
Storer 2004
Grinsp 1998
Grunfeld 2004
Bhasin 2000
Combined
Symbol
Individual

113. Prostate Events

114. Cardiovascular Events

115. Hematocrit Greater than 50%

116. Testosterone Effects on HRQOL: Rationale
Lean body mass is an important determinant of HRQOL in HIV-infected individuals (Wilson et al, 1999)
Testosterone improves LBM and HRQOL in HIV-infected men (Grinspoon et al, 1998)
Aging-associated impairment of physical function is associated with significant decrease in overall HRQOL (Wier et al).
TRT improves rehabilitation outcomes in ill, older men (Bakhshi et al, 2000).

117. Effects of Testosterone Replacement in Older Men with Low or Low Normal T
Study
Subjects
Treatment Regimen
 in Body Comp
 in Muscle Function
Comments
Tenover, et al
1992
60-75 y/o
T<400 ng/dL
TE 100 mg/wk for 3 months
1.8 kg  in FFM
No  in FM
No  in grip strength
Mild  in PSA and HCT
Morley, et al
1993
69-89 y/o
BT<75 ng/dL
TE 200 mg/2 wks for 3 months
No  in FM or body weight
 in grip strength -
Sih, et al
1997
Healthy, y/o
BT<60 ng/dL
TC 200 mg/2 wks for 12 months
No  in body comp
4-5 kg  in grip strength
No  in PSA  in HCT

118. Effects of Testosterone Replacement in Older Men (cont)
Study
Subjects
Treatment Regimen
 in Body Comp
 in Muscle Function
Comments
Urban, et al
1995
Healthy, >65 y/o
T <480 nd/dL
TE weekly for 4 wks to  T to ng/dL
Body comp not reported
 hamstring & quadriceps strength
2-fold  in muscle protein synth. rate
Snyder, et al
1999
Healthy, >65 y/o
Scrotal T patch 6 mg/day for 3 yrs
 LBM kg
FM  3 kg
No  in knee extension & flexion
Improved perception of physical function
Tenover
2000
Healthy, older men
TE 150 mg/2 wks
for 3 yrs
 FFM
 FM
Improved grip strength -

119. T and DHT induce nuclear translocation of -catenin
Control
40x
DHT 10nM
T 100nM
DHT 10nM+BIC 100nM
BIC 100nM
Red: -catenin (Texas Red)
Blue: counterstain (DAPI)

120. Effects of Testosterone Replacement in Older Men (cont)
Urban et al 2002
Older men with T<17 nmol/L
TE variable dose
Incr. FFM
Incr. muscle strength
Incr. IGF-1 and AR expression
Kenny et al, 2001
77 older men bioT <4.4 nmol/L
T patch 5 mg/d or placebo
+1 kg Incr. In FFM, 2% decr. in FM
Incr. In muscle strength
Incr. BMD

121. Study Design GnRH TE Expected Group Agonist Dose T conc.
I + 25 mg 175 ng/dL
II + 50 mg 350 ng/dL
III mg 800 ng/dL
IV mg 1400 ng/dL
V mg 2500 ng/dL

122. Summary of Adverse Events
Numerically, greater number of adverse events and SAEs in older men than younger men: not statistically significant.
None of the younger men had a SAE.
The AE profile was different in young and older men:
Young men had a higher frequency of acne than older men.
Older men had higher frequency of Hct >54%, edema, CHF, and prostate events than young men.
Most frequent causes of treatment discontinuation in older men were Hct >54% and leg edema; these AEs were dose related.
Therefore, DSMB discontinued 600 mg dose in older men in Dec

123. Dose-Selection: Trade-Off Between Adverse Effects and Beneficial Effects
Higher the dose, greater the anabolic effects, and higher the frequency of adverse events
Best trade-off was achieved at 125 mg/week TE dose; this dose was associated with:
Very low frequency of AEs
Serum T levels in the high normal range
Average 4.2 kg increase in FFM
Average 28 kg gain leg press strength

124. Role of Testosterone in Spontaneous vs Induced Sexual Response
Compared to eugonadal men, hypogonadal men had:
Lower self-reported sexual activity, feelings and thoughts
Lesser number of spontaneous erections
Similar erectile response to visual erotic stimulus
Testosterone replacement for hypogonadal men:
Increased sexual feelings and thoughts, and sexual activity
Increased number of spontaneous erections
But did not change erectile response to visual erotic stimulus
Spontaneous, but not stimulus-induced, erections
are testosterone dependent
Testosterone stimulates sexual thoughts and feelings
Kwan et al, J Clin Endocrinol Metab 1983;57:557-62

125. Forest Plot of Mean Difference for FFM Change
-6.0
-2.5
1.0
4.5
8.0
Mean Difference
Study
Bhasin 1998
Storer 2004
Bhasin 2000
Grinsp 1998
Combined
Symbol
Individual

126. Mechanisms of Anabolic Effects on the Skeletal Muscle
The increase in muscle strength is proportional to the increase in muscle mass; specific tension does not change (Storer 2004)
T supplementation is associated with dose-dependent increase in hypertrophy of both type I and II fibers (Sinha-Hikim 2002).
T-induced muscle hypertrophy is accompanied by an increase in the number of myonuclei and satellite cells (Sinha-Hikim 2003)

127. T Supplementation in Older Men: The Issue of Our Times
T prescription sales in the USA in 2004 >600 million dollars; 26-fold increase since 1993
>1000 T-related stories in the media

128. Change in Total T in Young and Older Men Treated with GnRH-A + TE
T dose effect, P<0.0001
Age effect, P<0.0001
Change in T (ng/dL) 25 50
125
300
600
TE (mg)

129. T Dose Response in Young and Older Men: Change in Fat Mass (DEXA)
(kg)
T Dose Effect P <0.0001
Age effect P<0.001
T Dose (mg)

130. Age-Related Decline in Lean Mass and Muscle Strength (BLSA; Roy et al 2002)
Quadricepes and Biceps Strength (N)
Leg and Arm Lean Mass (kg)
Age (years)
Age (years)

131. Powerful Demographic Trend Towards Aging of Human Populations
Physical dysfunction
Increased health care $$$$$$
Sexual dysfunction
Poor HRQOL
Growing populations of older men and women around the globe
Cognitive impairment

132. Is Testosterone the Fountain of Youth?

133. Testosterone and Cognition: Intervention Studies
Study Intervention Patients Results
Alexander T replacement hypogonadal Incr. verbal men fluency
Van Goozen T replacement Trans-sexual Incr.Spatial cognition
Janowsky T replacement Healthy older Incr. spatial men cognition
Janowsky T replacement Healthy older Improved
men working memory
Cherrier T replacement Older men Improved verbal memory and fluency

134. Testosterone Effects on Mood
Clinical Experience:
Hypogonadal men report marked improvement in sense of wellbeing, energy, and mood after initiation of T therapy
T therapy improves positive aspects of mood and decreases negative aspects of mood in hypogonadal men (Wang et al, JCEM 1996)
No RCTs in older men

135. Total Serum T Levels in Young and Older Men Treated with GnRH-A + TE
T dose effect, P<0.0001
Age effect, P<0.0001
Serum T (ng/dL) 25 50
125
300
600
Bhasin et al JCEM 2005
TE (mg)

136. T Effects on Bone Outcomes
No data on bone fractures
Two trials of 3-years duration showed a moderate effect on lumbar bone density (0.4, CI 0.1,0.7) (Snyder 1999; Amory 2004)
Ruled out a moderate treatment effect on femoral neck bone density (0.0, CI -0.3, 0.3)
Montori 2005

137. Rationale for T Supplementation in Older Men: Hypotheses
T levels decline with advancing age.
Low T associated with adverse health outcomes
T supplementation improves physical, sexual, cognitive function, QOL and other health-related outcomes
Testosterone administration is SAFE.

138. Epidemiological Data: Weak Association of Low T and Outcomes
Directly associated with:
Muscle mass (Baumgartner 1998; Melton 2000),
Strength of knee extension (Morley 2000)
Self-reported physical function (MMAS 2005)
Sexual desire (Beutel 2005)
BMD, vBMD and bone geometry (Khosla 2005)
Inversely associated with:
CAD (Wu 2003; von Eckardstein 2003)
Visceral fat (Seidell et al)
Mortality (Shores et al 2006)

139. Inconsistent or No Association
Aging-related symptoms (T’Sjoen 2004)
Prostate volume or LUTS (Schatzl 2000)
Erectile Dysfunction (Korenman, 1996 ; Morley 1997)
Depression indices (Seidman 2001; Barrett-Connor 2001; Schatzl 2000)

140. Effects of T Therapy on Erectile Function and Libido
Bolona et al. (unpublished)

141. Sexual Function: A Complex, Multi-Component System

142. Effects of Castration on Life Span and Cardiovascular Mortality
Studies of “castrati” singers
Nieschlag (1993): no difference in life span between 50 castrated and 50 intact opera singers
Jenkins (1998): no difference between life span of 25 castrated and 25 intact singers
Studies of castrated, institutionalized men with behavioral problems (Hamilton and Mestler, 1969)
Median life span greater in castrated men (69 yrs) than intact men (56 yrs)
Models of life span extension have low levels of sex hormones and growth factors (Bartke et al, 2002)

143. Testosterone Increases Attentiveness to Erotic Stimuli
David:
Previous slide note on bottom of slide says testosterone does not enhance stimulus-induced erection. This slide talks about sexual arousal (presumably erection) in response to auditory stimulus?
Testosterone Increases Attentiveness to Erotic Stimuli
Testosterone replacement therapy in hypogonadal men increases:
Attentiveness to sexual stimulus in dichotic listening/selective attention task
Alexander et al, Horm Behav 1997;31:110-9.

144. Testosterone Effects on Cognition
Question: To determine effects of T on cognitive abilities in healthy older men
Design: Placebo-controlled, double-blind, randomized.
Groups: TE 100 mg weekly vs. placebo X 6-wks
Results: improvements with TRT in
spatial memory (recall of a walking route)
spatial ability (block construction)
verbal memory (recall of a short story)
Cherrier et al, Neurology 2001;57:80-8

145. T Dose Response in Young and Older Men: Change in Hamilton Depression Rating
Score
Age effect = NS
Dose Effect = NS
T Dose (mg)

146. Meta-analysis Plot of Fat Mass Change in Older Men
T deceases fat mass
Bhasin Nature CPEM 2005
Mean Difference in Fat Mass (kg) Change between Placebo and T Groups

147. TESTOSTERONE TRIAL EFFECTS OF TESTOSTERONE ON PHYSICAL FUNCTION IN OLDER MEN
(Page, S. T. et al. J Clin Endocrinol Metab 2005;90: )