hypogonadism: controversies of diagnosis and treatmentcontroversies) late onset...

Hypogonadism:

Controversies of Diagnosis

and Treatment

Ronald Swerdloff MD

Professor of Medicine

Harbor-UCLA Medical Center

David Geffen School of Medicine

at UCLA

Conflicts of Interest

AbVie Consultant

Besins Consultant

Clarus Consultant,

Lipocene Grant Recipient

Lilly Consultant

TesoRex Consultant

Quest Consultant

NIH, NIA Grant Recipient

Testosterone Treatment

It all Began Here in 2000

http://www.time.com/time/magazine/0,9263,1101000424,00.html

http://www.time.com/time/magazine/0,9263,1101000424,00.html

spermatogenesis

cognition

increase bone mass

Fat decrease fat mass

*

*

*

* May require

conversion to E2

*

How Much Of Low T

Syndrome is Low E2?

Tale for a Different Time

Is Age Associated Low T

Syndrome a Real Disorder?

For Sure but Who to Treat?

Male Hypogonadism

Often Considered as a Sexual Disorder

Most symptoms Are Systemic and

Overlap With Other Conditions:

• Decreased libido

• Loss of vitality

• Visceral obesity

• Decrease muscle mass and strength

• Osteopenia and bone pain

• Mood changes and depression

Challenges in Diagnosis

of Male Hypogonadism

If symptoms of testosterone

deficiency are non-specific, then

the diagnosis requires

testosterone measurements

Testosterone Deficiency

Laboratory Diagnosis

1-2 % of testosterone is free

(unbound)

30 to 50 % is bound to albumin with

low affinity

• Free and albumin bound T are

bioavailable

• 40 to 50% is bound to Sex Hormone

Binding Globulin (SHBG)

Total T

100%

SHBG

ALB

Free

Bio

availa

ble

T

Tota

l T

SHBG Rises With Age

SHBG Falls With Obesity

Laboratory Tests in Suspected

Hypogonadism

• When to draw sample?

• How many samples?

• What assays to use?

Testosterone DeficiencyLaboratory Diagnosis

• Method: LC/MS/MS is the gold standard.

• H-UCLA uses Immuno-metric method.

Confirm Low Value

• Diurnal Variation in T levels: Draw blood between 7 and 10 AM

• Clinicians need to know the reference range for the laboratory and the method they are using. Reference ranges are on AM samples

What About Borderline T

with Symptoms?

Measure Free Testosterone

freeT Assay

Suggest ordering a free

testosterone

by the:

Free T Dialysis Method

Do You Measure Total T or

freeT to Diagnose Late

Onset Hypogonadism?

Guidelines say Total T

first

freeT as secondary?

What Happens to Serum

Testosterone Levels in Men

When they Age?

Low T or Free T Index in Aging men

(% of Men Below the Young Adult

Male Reference Range)

0

10

20

30

40

50

60

70

80

90

100

20-29 30-39 40-49 50-59 60-69 70-79 80+

T

fTindex

%

Adapted from Harman JCEM 2001Age

18 201279

332

350

251

94

Age (Years)

To

tal Te

sto

ste

ron

e (

ng

/mL

)

0

2

4

6

8

20-29 30-39 40-49 50-59 60-69 70-79 80-89

oo

o

o

o

o o

o

o

o

o o o o

oo o

o

o

o

o

o

o

o

o

o

oo

o o

Comparison of Testosterone Decline with

Ageing in Men from Six Longitudinal Studies

MMAS (n=1709)BLSA (n=1002)Rancho Bernardo (n=856)

Brazil (n=965)Vermeulen (n=250)Morley (n=336)

o

(Mohr et al 2005)

Pathological hypogonadal range

How Common is low T in

the General Population of

Elderly Men?

Percentage of Men greater

than 65 Years with

Repeatable low T and

symptoms is < 5%

40 - 50 - 60 - 70 - 80 years

2-3 4-7 15-22 35-55 %

Testosterone deficiency in

SHBGTestosterone

What is the Serum T

Threshold for Low T

Symptoms?

What Level of Testosterone is

Clinically Relevant

For the Diagnosis?

• There have been efforts to relate

symptoms and signs of

hypogonadism to serum

testosterone.

• The best data in middle aged and

older men comes from the

European Male Aging Study (EMAS)

Testosterone (Total & Free) Thresholds for

Symptoms of Androgen Deficiency (n = 3219)

Wu et al. N Engl J Med 2010;10.1056

Threshold for Serum

Testosterone and Symptoms

• The problem is complicated by the

concept that there are individual

patient differences in sensitivity to

serum testosterone.

Reference range 300-

1000 ng/dL

Can you rank these

young adult men by T

Level?

How Do You Diagnose T

Deficiency in Elderly Men?

• Signs and/or symptoms of androgen deficiency.

• A reproducibly low measurement of serum T or its biologically active component is required.

Bhasin et al 2010; Wang et al,2008

Does Treatment with

testosterone improve

symptoms?

-If so-What symptoms?

-If so, who (what levels of

baseline serum T) benefits?

-If improvement is not uniform ,

how do you predict candidates?

Direct To Patient Marketing

Good or Bad?

Patient Centric Medicine: Empowering

the patient?

Is this patient awareness?

“Ask your Dr if you have Low T?”

• FDA suggests that marketing creates

diseases (Low T Syndrome) and sells

unnecessary and possibly dangerous

drugs (Testosterone)

Direct to Patient Advertising

Clinical Disorders and Products

Examples of supportive beneficial

data

Benefits of T Treatment of LOH

Is it real or just fluff?

Testosterone and Body

Composition

Androgen

deficiency is

associated with:

increase in body fat;

decrease in fat free

mass; decrease in

muscle protein

synthesis

Testosterone Treatment of

Elderly Men

1.0

0.0

-1.0

-2.0

-3.0

-4.0

3624120Time (months)

Snyder PJ, et al. J Clin Endocrinol Metab. 1999;84:2647-2653

Testosterone

Placebo

Ch

an

ge i

n F

at

Mass (

kg

)


Elderly Men

2.5

1.5

1.0

0.5

0.0

-0.5

3624120

Ch

an

ge i

n L

ea

n M

as

s (

kg

)

Time (months)Snyder PJ, et al. J Clin Endocrinol Metab. 1999;84:2647-2653

2.0

Testosterone

Placebo

Hypogonadism and Bone

Density

µ-MRI Virtual Bone Biopsy

Eugonadal Man

(28 yrs, Caucasian)

Hypogonadal Man(31 yrs, Caucasian)

Benito M, et al. J Clin Endocrinol Metab. 2003;88(4):1497-502.

Amory JK, et al. J Clin Endocrinol Metab 89:503-510, 2004

Changes in Lumbar Spine BMD

with TRT in Aging Men

BM

D (

% C

han

ge)

Study Month

0

14

12

10

-2

8

6

4

2

-4

0 10 20 30 40

Placebo

T+F

T only

Mean +/- SEM

Overall Sexual Desire Score is

Maintained in Hypogonadal Men after

Treatment with T-Gel for 3 Years

Month

0 6 12 18 24 30 36

Se

xu

al

De

sir

e(0

-7)

1

2

3

4

Wang et al. J Clin Endo Metab 2004;89:2085-98

Pathogenesis of Erectile

Dysfunction

Psychogenic

NeurogenicArteriogenic

Cavernosal

Defect NOHypogonadism

Erectile Dysfunction

Medication

Induced

What is the Benefit/Risk of

Treating Older Men with

Symptoms of Low T?

Is Tesosterone Dangerous

or Beneficial to the:

Heart?

Prostate?

Looks Very Positive

but

Observational (Open Label)

Data while Encouraged by

Regulatory Agencies for

Safety Clues are of Limited

Scientific Value

Potential Risks of T treatment of

LOH

• Cardiovascular

• Prostate

• Erythrocytosis

• Others

How Good Is the Evidence?

Is Low Testosterone

Good or Bad for an Adult

Man?

Epidemiologic Data

Low Testosterone is Associated with

Increased Mortality in Older Men

Study

Design

Number of

subjects

Follow

up

(years)

Mortality Hazard Ratio

(95% CI)

Recent

Studies

Retrospective 858 8 All-cause 1.88 (1.34-2.63)* Shores et al

Prospective 794 20 All-cause

CVD death

1.40 (1.14-1.71)*

1.38 (1.02-1.85)*

Laughlin et al

Prospective 2314 10 All-cause 2.29 (1.60-3.26)* Khaw et al

Prospective 1954 7.2 All-cause 2.32 (1.38-3.89)* Haring et al

Prospective 930 6.9 All-cause

in men with

CVD

2.27 (1.45-3.60)* Malkin et al

Survival and Low Testosterone in

Male Veterans

Low

testosterone

levels were

associated with

increased

mortality

(hazard ratio,

1.88; 95% CI,

1.34-2.63;

P<.001) Shores et al, Arch Int Med,

2006

Normal T

Low T

Cardiovascular Adverse Events in T

Rx of Older Men with Limited

Mobility ( TOMS Trial))

• 209 men, mean age 74 years

• At baseline, high prevalence of hypertension, diabetes, hyperlipidemia, obesity

• Transdermal T 10g /day and then dose adjust

• More cardiovascular adverse events (23) in testosterone treated versus (5) placebo group. Study stopped

Basaria et al NEJM 363:109, 2010

Bremner NEJM 363:189, 2010

Cardiovascular Adverse Events in T

Rx of Older Men with Limited

Mobility ( TOMS Trial))Problems with Study

• Small size

• High prevalence of chronic disease

• Starting transdermal T dose high and 72%

of subjects received 10g/day or more

• Men with the highest quartile of serum T

levels had increased risk (hazard ratio 2.4)

for cardiovascular adverse event

Basaria et al NEJM 363:109, 2010

Bremner NEJM 363:189, 2010

Testosterone-treated Men Had a Longer

Survival Than Untreated Hypogonadal Men (P

= 0.029).

Shores M M et al. JCEM, 2012

Treated with T

n=398

Not treated with

T, n= 633

T-Treated Men: Lower Survival Than

Untreated Hypogonadal Men (VA)

Treated with T

n=1223 at start, 61

at end

Not treated with T, n=

7486 at start, 206 at end

Vigen et al, JAMA Nov. 2013

Testosterone and Cardiovascular

Disease Risk • 8709 men with low testosterone <300ng/ml

who underwent coronary angiogram

• 1223 received testosterone therapy

• Testosterone use was associated with

increased risk of all-cause mortality,

myocardial infarction, and ischemic stroke

(Hazard ratio 1.29, 95% CI 1.04 -1.58)

• Manuscript was criticized by many letters to

the editor, authors corrected errors in the

published manuscript

Vigen et al, JAMA Nov. 2013

Death by Testosterone?

We Think Not!

Traish AM, et al. J Sex Med 2014;11:624-629

Testosterone Therapy and

Cardiovascular Events Among Men: a

Systematic Review and Meta-analysis

of Placebo-controlled Randomized

Trials

Lin Xu, Guy Freeman, Benjamin J

Cowling and C Mary Schooling

Xu et al. BMC Medicine 2013 11:108

Testosterone Therapy & Cardiovascular

Events Among Men: a Systematic Review

and Meta-Analysis of Placebo-Controlled

Randomized Trials

Xu et al. BMC Medicine 2013 11:108

• 27 trials, over 25 years

• 2994 mainly older men experienced 180 CV

events

• Overall CV risk increased with T therapy

Odds Ratio 1.54 (95% CI 1.09-2.18)

• CV event rate was lower in trials funded by

pharmaceutical companies

Problems: AE reporting and coding; many

small studies: CV risk was not primary

endpoint

Increased Risk of Non-Fatal Myocardial

Infarction Following Testosterone

Therapy Prescription in Men

• William D. Finkle, Sander Greenland,

Gregory K. Ridgeway, John L. Adams,

Melissa A. Frasco, Michael B. Cook,

Joseph F. Fraumeni Jr, Robert N. Hoover

PLOS One January 2014 Volume 9 Issue 1 e85805

Increased Risk of Non-Fatal Myocardial



• Large database of initial testosterone

prescriptions (n=55,593)

• Compare non-fatal myocardial infraction

within 90 days following the initial

prescription to rate in 1 year prior to

prescription; also compare with pre and

post-rates in PDE5I prescription

Finkle et al PLOS One 9:e85805, 2014



• Results: post/pre-prescription rate ratio

(RR) for TT prescription was 1.36; Men

aged ≥ 65 RR was 2.19 for TT pts and 1.15

for PDE5 I, RR for TT prescriptions

increased with age (0.95 for men < 55 yrs

to 3.43 for pts ≥ 75 yrs). In men< 65 yrs,

excess risk was confined to those with a

prior history of heart disease,WD Finkle, et al. PLOS ONE, Jan 2014, Vol 9, Issue 1 e85805



• Conclusion of Authors: “In older men

and in younger men with pre-existing

diagnosed heart disease, the risk of

MI following an initial TT prescription

is substantially increased.”

WD Finkle, et al. PLOS ONE, Jan 2014, Vol 9, Issue 1 e85805

BUT - - -

(based on the FDA statement)

• Trials were very heterogeneous and might

not be suitable for integration. Heterogeneity

in age, inclusion and exclusion criteria, study

duration, formulation, dose, baseline CV risk

• Broad outcome definition. Composite

outcome included more than 20 categories

including bleeding esophageal varices,

pericarditis, peripheral edema, aortic

aneurysms, hypotension, syncope, to death

from MI, giving each equal merit.

BUT - - -


• Not clear that all studies had full adverse

event reporting. Reported incidence of

cardiovascular-related events ranged from

<1% to 45%.

• Few of the articles in the meta-analysis pre-

specified CV safety outcomes or verified

these events by hospital records.

• Excluded trials of < 12 weeks duration but

did not specify how many

Current Conclusions

• Studies not designed to

examine testosterone effect on

CV risks

• Not prospective randomized

control trials, many studies

have small number of subjects

• Problems with meta-analyses

and cohort studies

Current Conclusions (cont)

• Need prospective RCT designed to

address whether testosterone

treatment will increase CV events

defined a priori

Continue testosterone substitution in

symptomatic hypogonadal subject

following society guidelines but share

with patient current information on

possible CV risk

Prostate Gland and

Testosterone

The billion dollar question:

Will testosterone treatment

increase the risk of prostate

cancer or BPH?

Another Tale To Tell

Summary

• Testosterone deficiency is associated

with clinical signs and symptoms

involving many organ systems

• Testosterone Rx of young and middle

aged hypogonadal men is standard

therapy with established benefitsRSS 2006

FDA, Lawyers, Clinicians,

Patients

Summary

• Inadequate data are available to prove efficacy of Testosterone Rx in all parameters in older men but some question whether hypogonadism in older men is different in its clinical implications and risk/benefit ratio from other age groups

RSS 2006

The Testosterone

(“T”)Trial

A Study of Men’s

HealthA joint effort of the University of

Pennsylvania, 12 Research Academic

Centers, and the National Institutes of

Aging, heart and Lung and Mental Health

at the

National Institutes of Health

Thank You!


Symptomatic Older Men With Low

Serum Testosterone

• A large Double Blind Placebo Controlled

interventional pharmacogenetic study (T

Trial) began in 2010 (sexuality, vitality,

muscle function, cognition) ( secondary

outcome- CAD)

Add on studies: BMD, Erythrocytosis,

NAFLD

Overview of the T-Trial• At each study site, 7 separate (but

coordinated) clinical trials– Physical function

– Sexual function

– Mental function

– Vitality

– CV function

– Anemia

– Bone density

• Enroll in 1 or more of these trials if qualified and consent to participate

• 65-70 men enrolled at LA Biomed site (total of 800 across all sites)

Special Tests

• CV Function:

-blood tests for lipids and inflamation;

-CT Angiography

• Anemia

• Bone Mineral Density

• Visceral Obesity & Steatohepatosis

• Pharmacogenetics (GWAS)

Androgen Treatment for the

Hypogonadal Elderly Man

• Treatment should be reserved for men with signs or symptoms of testosterone deficiency

• Benefit profiles may differ for older vs younger hypogonadal men

• Treatment policies should be evidence based

• We should avoid age bias in our medical decision making

Currently Available Androgens

• Oral

• Injectable

• Implants

• Transdermal

• Transbuccal

What are the Absolute and Relative

Contraindications to TRT?

Absolute:

• Documented prostate cancer

• Documented breast cancer

• Hematocrit = or > 55%

Relative:

• Hematocrit = or > 52%

• Untreated sleep apnea

• Severe obstructive symptoms of BPH

• Advanced congestive heart failure

OutlineMechanism of action of Androgen

Alternate androgens:

• Dehydroepiandrosterone (DHEA)

• Dihydrotestosterone (DHT)

• Testosterone (T) plus 5 alpha reductase inhibitor

• Selective androgen receptor modulators

Stimulation of Endogenous T production for secondary hypogonadism (normal or low LH/FSH)

• Human Chorionic Gonadotropin (hCG)

• Estrogen antagonist

• Aromatase inhibitors

spermatogenesis

cognition

increase bone mass

fat decrease fat mass

*

*

*

* May require

conversion to E2

*

Copyright ©1997 The Endocrine Society

Labrie, F. et al. J Clin Endocrinol Metab 1997;82:2396-2402

Serum DHEA,

DHEA-S in men

and women

Why DHEA as

androgen

replacement?

DHEA Treatment in Elderly Men

• In the absence of hypogonadism, DHEA

administration has a minimal if any

effect of serum testosterone levels

• Many small studies show either no

effect or some beneficial effects of

DHEA in men

• DHEA is readily available in health food

stores in the US

DHEAge Study in Elderly Men

and Women

• France 1998-1999

• 280 elderly men and women, 140 men

and 140 women, half between 60-69 and

half between 70 and 70 years

• Placebo controlled, double blind study

• DHEA 50 mg or placebo given per day

(Akzo lab) for 12 months

Baulieu et al, PNAS, 2000

DHEAge Study in Elderly Men

and Women

• In men, serum DHEA levels were

increased but no increase in serum T or

androstanediol G.

• No effect on BMD, some effect on skin.

• There was no change in muscle

strength (handgrip and isokinetic knee

strength) or fat and muscle cross

sectional area of the thigh

Baulieu et al, PNAS, 2000

DHEA in Elderly Women and Men

• Subjects: over 60 years, low bioavailable T and low DHEA in men; (cutoffs were 15th percentile of those of young men or women)

• Men – DHEA 75 mg + transdermal placebo patch , placebo tablet + 5mg /day T patch, or placebo tablet +placebo patch

(Nair et al 2006)

DHEA Treatment of Elderly Men

• Despite return of DHEA levels to the young

adult range, DHEA had little effect on body

composition, no significant effect on muscle

strength

• DHEA had no effect on peak VO2, muscle

strength, quality of life or insulin resistance

• DHEA had minor effects on BMD, these could

be related to the small increases in estradiol

found after DHEA treatment

• Administration of DHEA had few adverse

events

DHEA Treatment of Elderly

Women and Men

Editorial:

• Nair et al study confirmatory of the French DHEAge study

• Muller showed no changes in muscle power and frailty between DHEA and placebo group (JCEM 91: 3988-3991)

Dihydrotestosterone (DHT) Instead

of Testosterone (T) for Replacement

• Two concerns:

– Effect of high serum DHT on intraprostatic

DHT and prostate growth (DHT is 10 fold

higher in the prostate than T)

– DHT is not aromatizable and serum

estrogens will be low, may have negative

effect on bone

3 b-Androstanediol and ER b Regulates

Prostate Growth

T DHT

AR

Proliferation

5a androstane

3b- 17b diol

ER b

Excretion

ER a not

in

Prostate

6a & 7a

triols

E2

5a

reductase3 b HSD

(Gustaffason et al 2001)

DHT Administration in

Older Men

• In older hypogonadal men, two placebo-controlled short term studies showed some improvement in sexual function and strength and decrease in fat mass ( Ly et al, 2001; Kunelius et al, 2002)

• In older men there were no changes in mood, mobility, balance, cognition (MMSE), quality of life assessments

• No change in prostate volume

• No report on BMD

Trough Serum DHT and DHT + T Levels in Older

Men after transdermal application of DHT Gel

DHT

Month

0 6 12 18 24 30 36

DH

T(n

mo

/L)

0

4

8

12

16

20

All Subjects

Normal Range

DHT+T

Month

0 6 12 18 24 30 36

DH

T+

T(n

mo

l/L

)

0

10

20

30

40

50

73

63

58

5225

47

33

Wang et al, unpublished

Body Composition Changes in Older Men

After Transdermal Application of DHT Gel

Total Body Mass

Month

0 6 12 18 24 30 36

Bo

dy M

as

s C

ha

ng

e(k

g)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5 Lean

Month

0 6 12 18 24 30 36

Le

an

Ch

an

ge

(kg

)

0.0

0.5

1.0

1.5

2.0

2.5

3.0Fat

Month

0 6 12 18 24 30 36

Fa

t C

ha

ng

e(k

g)

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

p<0.001

p<0.003

p<0.0001

Hip and Spine BMD Levels in Older

Men After Transdermal DHT Gel

Hip

Month

0 6 12 18 24 30 36

Hip

BM

D(g

/cm

3)

0.80

0.85

0.90

0.95

1.00

1.05Spine

Month

0 6 12 18 24 30 36

Sp

ine B

MD

(g/c

m3)

0.90

0.95

1.00

1.05

1.10

1.1573 56

3822

p=0.06p=0.80

Serum PSA Levels, IPSS Score and

Prostate Volume in Older Men After

Transdermal Application of DHT Gel

PSA

Month

0 6 12 18 24 30 36

PS

A(n

g/m

L)

0

1

2

3

4

5

IPSS

Month

0 6 12 18 24 30 36

IPS

S(s

co

re)

2

3

4

5

6

7

8

9

10Prostate Volume

Month

0 6 12 18 24 30 36

Vo

lum

e(m

m3)

30

32

34

36

38

40

42

44

p=0.02

p=0.15

N.S.

2 out 73 subjects was diagnosed with prostate cancer during the study

Summary• DHT Gel in Older Men Resulted in Small

Increases in Lean Mass, and Early Decreases in fat mass that were later regained.

• Serum bone specific alkaline phosphatase steadily increased by 16% per year (p<0.0001). BMD did not decrease in the spine, but appeared to show a decreasing trend in the hip (p=0.06).

• Prostate volume was not increased. PSA increased over 3 years (p=0.02) at a mean velocity of 0.15 ± 0.05 ng/dL per year.

• No unanticipated adverse events related to DHT treatment occurred.

• No advantage over T replacement

5 alpha reductase inhibitor and oral T

Dutasteride enhanced

serum T levels in men

with induced

hypogonadism after oral

T treatment

Amory et al, JCEM 2005

5 alpha reductase inhibitor and oral T

Dutasteride decreased

serum DHT levels in men

with induced

hypogonadism after oral

T treatment

Amory et al, JCEM 2005

5 Alpha Reductase Inhibitor and Oral

Testosterone

• Increases serum testosterone levels

after oral administration

• Attenuates the increases in serum DHT

• Low intraprostatic DHT levels

• May provide oral, selective form of

androgen delivery

• Long term safety and effect on prostate

growth have to be studiedAmory et al, JCEM 2005

Selective Androgen Receptor

Modulators (SARMS)

• Act co-activators or modulators of co-activators or co-repressors of the androgen receptor

• May not be converted to estrogen or 5 alpha dihydrotestosterone

• May show different tissue specificity

SElective Androgen Receptor

Modulators (SARMS)

• Oral agents, steroidal or non-steroidal

• Potential of having beneficial effects on androgens on muscle, bone and without effects on the prostate and the lipids

• In phase 1 to 3 clinical trials

(Narayama et al, 2008; Dalton et al, 2011; Miner et al, 2007, Schmidt, 2010; Basaria et al, 2012; Nagata et al, 2011)

SARMs Within the Androgen

Receptor

DHT Enhanced

SARM

SARM

Mohler et al, J Med Chem 2009

SARM –GTX024• Selective action on anabolic tissues

• Older men and women (n=60) Placebo

controlled clinical trial

- Increase lean mass and decrease fat

- Improve physical performance

- No serious adverse effects, no effect in

free T or LH (Dalton et al 2011)

• Cancer Cachexia (n=100)

– Increase lean body mass

– Increase muscle function (stair climb)

(Morton et al ENDO 2009)

SARM: LGD 4033 in Healthy Men

–Pharmacokinetics at Day 21


Pharmacodynamics

Basaria et al 2012

Serum T is suppressed but serum LH is not

suppressed and serum FSH is suppressed

only by the high dose


-Pharmacodynamics

Basaria et al 2012

Serum free T is suppressed only in the high

dose. Serum SHBG is dose dependently

suppressed. This suggests that the low serum

T may be due to the low SHBG.


–Lean Body Mass (after 3 weeks)

Basaria et al 2012

Lean Mass

SARM: LGD 4033 in Healthy

Men – Fat Mass

Basaria et al 2012

Fat Mass


– Change in Serum Lipids

Placebo 0.3 mg 0.3 mg 1.0 mg

Total

Cholesterol

(mg/dl)

-1.6 -10.8 -18.0 -14.3

HDL

(mg/dl)-1.7 -1.0 -10.4 -19.4

LDL

(mg/dl)0.9 -5.5 -2.8 7.1

Triglycerides

(mg/dl)-4.3 -21.4 -24.0 -10.1

Basaria et al 2012

Oral SARMs

• Not converted to estrogens

• Dose dependent significant decreases in

serum HDL-cholesterol

• Marked suppression of serum T and

probably of estradiol, effect on bone

• Marked suppression of SHBG – effect on

metabolism (Low SHBG associated with

Metabolic Syndrome and Type 2 Diabetes)

SARM for Hypogonadism

• Many different molecules

• Developed by industry (e.g. Ligand,

Merck, GTX, Lilly )

• Sarcopenia, Cachexia (short term

treatment)

• Long Term study to show tissue

specificity, improved efficacy, and

minimal side-effects (lowers HDL-

cholesterol, increases hemoglobin)

Adapted from Bagatell CJ, Bremner WJ. N Engl J Med.

1996;334:707-714.

GnRH

LH FSHTestosterone

Testosterone

Sperm

Hypothalamus

Pituitary

Testis

Estradiol

Estradiol

Requires relatively intact

hypothalamus-pituitary

axis

Estrogen antagonist

Aromatase inhibitors

hCG

rHCG In Older Men

• Randomized double blind placebo

controlled randomized trial

• rhCG 5000 IU sc twice /week for 3

months

• 40 men (60-80 years, mean 67year) with

serum T less than 15 nmol/l (430ng/dl)

• Outcome variables: body composition,

muscle strength, physical activity,

sexual function, safety parameterLiu et al, JCEM, 2002

LH*

U/L

-6

-4

-2

0

2

FSH*

Time (months)

0 1 2 3 4

U/L

-8

-4

0

4

Total Testosterone*

nmol/L

0

8

16

Free Testosterone*

pmol/L

0

100

200

300

Estradiol*

Time (months)

0 1 2 3 4pmol/L

0

100

200

Treatment

rHCG In Older Men Liu et al, JCEM, 2002

Lean Mass*

Time (months)

0 1 2 3 4kg

-2

0

2

4

Weight*

-1

0

1

2

Body Composition

Body Fat

Time (months)0 1 2 3 4

%

-1.6

-0.8

0.0

Leptin

ng/mL

-2

0

2

rHCG In Older Men Liu et al, JCEM, 2002

rhCG in Older Men

• Increases serum T, free T and estradiol

• Increases body weight, lean body mass, and reduces body fat

• No changes in muscle strength or physical functioning

• No change in sexual activity

• No significant change in Hgb, PSA, IPSS; 3 in the rhCG group developed breast tenderness

Liu et al, JCEM, 2002

Clomiphene Citrate Increases Endogenous

Testosterone in Secondary Hypogonadism

• Partial estrogen antagonist

• Increases endogenous secretion of gonadotropins and testosterone

Guay et al, 1995

• 17 men with ED and secondary hypogonadism

• Double blind placebo controlled trial with clomiphene citrate Vs placebo for 2 months

• LH, FSH, T and free T increased in clomiphene citrate group

Shabsigh et al, 2005

• 36 men with serum T <300 ng/ml, mean age 39 years

• Clomiphene citrate 25 mg/day for 4-6 weeks

• Serum T increased from mean 248 + 40 to 610 + 179 ng/ml

• Ratio of T to E2 increased from 8.7 to 14.2

Clomiphene Citrate Increases Endogenous T

and Free T in Secondary Hypogonadism and

ED• 272 men with secondary hypogonadism and ED

• Mean age 54.3 years

• Clomiphene citrate 50 mg three times per week

• Adverse events not reported

Guay et al, Int J Impotence Res, 2003

Clomiphene Citrate Increases Endogenous LH and

Free T in Secondary Hypogonadism and ED

Irrespective of Clinical Response to Treatment

Guay et al, Int J Impotence Res, 2003

Serum LH

Serum Free T

Clomiphene Citrate in

Hypogonadal Men• Prospective study

• Hypogonadal men (n-86)

• Treatment duration (mean 19 month)

• Clomiphene citrate 25 mg every other

day titrating up if necessary

• Target serum testosterone 550 ng/dl

• ADAM questionnaire to assess

responseKatz et al, BJU Int., 2011

Clomiphene Citrate in

Hypogonadal Men

• Serum testosterone and gonadotropins

increased

• Improved ADAM questionnaire for at

least 3 questions

• No major side effects

Katz et al, BJU Int., 2011

Clomiphene Citrate Vs Testosterone

Gel Treatment of Hypogonadal Men

• Retrospective study, no placebo

control

• ADAM questionnaire as end point

• Testosterone gel (n=39) or clomiphene

(50 mg every other day, n=65)

• Similar levels of serum testosterone

• Improvement of symptoms same

• Cost per month Testim $270. Androgel

265, Clomiphene $83Taylor et al, J Sexual Med, 2010

Androxal

The Trans Isomer of Clomiphene

C C

Cl

RO

C C

Cl

RO

trans cis

R=(C2H5)2NCH2CH2

C C

Cl

RO

C C

Cl

RO

trans cis

R=(C2H5)2NCH2CH2

Repros Therapeutics Inc

Treatment of Secondary Hypogonadism with

Enclomiphene for 15 days

Effects on Change in Total Testosterone

12.5 mg 50 mg25 mg

Androgel 5g

Androgel 10g

Placebo

-50

0

50

100

150

200

250

300

350

400

Ch

an

ge

fro

m b

as

elin

e n

g/d

l Phase I/II Trial – Preliminary data

P=0.0053

P=0.0002 P=0.0005 P=0.019P=0.043

Enclomiphene PlaceboT gel

Preliminary Data Phase I/II

Repros Therapeutics Inc

Aromatase Inhibitors in Elderly Men

• Anastrozole is a potent aromatase inhibitor

• Decrease conversion of T to estradiol

• Increases T by decreasing negative feedback

at hypothalamus and pituitary

•37 men ( 62 to 74 y), serum T < 350 ng/dl

•Randomized to : Anastrozole 1 mg/day

(n=12)

Anastrozole 1mg twice/week

(n=11)

Placebo (n=14)

•Treatment for 12 weeks Leder et al, JCEM 2004


Placebo

Anastrozole

Placebo

Anastrozole

1mg/ 2x/wk

1mg/day

Leder et al, JCEM 2004


• Bone resorption markers remained stable (serum N-telopeptide, urinary deoxypyridinoline)

• Bone formation markers showed no change (serum osteocalcin and peptide of type 1 collagen)

• Total body BMD did not change in 12 weeks

Despite decreases in estradiol and increases in testosterone there were no effects on bone metabolism

Leder et al, JCEM 2004


• 10 young (20-33y) Vs 10 elderly men (68-81Y)

• Placebo or letrozole (2.5 mg/day) for 28 days

• Crossover study with 14 days wash out period

• Letrozole decreased serum estradiol by 46% in young and 62% in elderly men (p=0.03)

• LH increased by 339% in young and 323% in elderly (NS)

• T increased by 146% in young and 99% in elderly (NS)

• No effect of age on changes in hormone levels

T’Sjoen et al, JCEM, 2005

Anastrozole and T Vs T Alone in Men

With Epilepsy, Sexual Dysfunction

and Hypogonadism

• N=40 randomized, treatment 12 weeks

• All received T cypionate 300 mg every 2

weeks + Anastrozole 1 mg or placebo

• Anastrozole + T had more normalization

of sexual function (NS)

• Both groups had improvement of Beck

depression score and decreased seizure

frequencyHerzog et al 2010

Anastrozole and T Vs T alone in

Men with Epilepsy, Sexual

Dysfunction and Hypogonadism

• Sexual function score correlated

inversely with baseline and during

treatment

• Seizure frequencies correlated with

baseline estradiol

Herzog et al 2010

Aromatase Inhibitor for Male Infertility

and Klinefelter’s Syndrome

• Uncontrolled studies, case series

• Testolactone or Anastrozole or Letrozole

increased serum T levels despite presence of

elevated LH and FSH

• Moderate increase in sperm concentrations

and total sperm count/ejaculate

• Patients who responded with increase serum

T had better rate of sperm retrieval by TESE

for ICSI

(Clark & Sherins, 1989; Pavlovich et al, 2001; Patry et

al, 2002; Ramasamy et al, 2009, Saylam et al 2011 …)

SummaryAlternate androgens:

• DHEA – no use

• DHT – not likely to be useful alternative

• T plus 5 alpha reductase inhibitor – two medications

• SARMS – need Phase 3 long term clinical studies

Stimulation of endogenous T production

• hCG – need long term studies, ? any advantage over T in men not seeking fertility

• Estrogen antagonist and aromatase inhibitors

– ? need more long term studies in hypogonadal men, ? men with low or

normal LH and FSH levels

AE, adverse event; CVD, cardiovascular disease; TOM, Testosterone in Older Men With Mobility Limitations. Basaria S et al. N Engl J Med. 2010;363(2):109-122.

TOM Trial:

Cardiovascular Adverse Events

Caution is warranted in interpreting and extrapolating

from these findings to other doses and formulations

of testosterone or to other populations, particularly

men with hypogonadism without CVD or mobility

limitations

Participants had high prevalence of chronic

conditions, including preexisting heart disease,

obesity, diabetes, and hypertension

Cardiovascular AEs were not a planned primary or

secondary outcome, and therefore, a structured

analysis of cardiovascular AEs was not performed

TOM Trial:

Cardiovascular Adverse Events

Clinical characteristics of the study population

differ from those of most other populations in

which testosterone therapy has been

administered in a clinical setting or as part of a

clinical trial

Trials terminated early tend to overestimate

treatment differences

Trials that lack a consistent pattern in AEs and

a small number of overall AEs suggest the

possibility that the differences detected

between the two groups may be due to chance

AE, adverse event; CVD, cardiovascular disease; TOM, Testosterone in Older Men With Mobility Limitations. Basaria S et al. N Engl J Med. 2010;363(2):109-122.

Association of Testosterone Therapy With

Mortality, Myocardial Infarction, and Stroke

in Men With Low Testosterone Levels

• Purpose: to determine the association

between testosterone therapy and all-

cause mortality, MI and stroke in male

veterans

• Retrospective national cohort study of

men with low T levels (<300 ng/dL) who

underwent coronary angio at a VA

2005-2011.R. Vigen et al. JAMA 2013;310:1829-36

Association of Testosterone Therapy With

Mortality, Myocardial Infarction, and Stroke

in Men With Low Testosterone Levels

• 8709 men with low T; 1223 pts started on

T therapy after a median of 531 days post

angiography.

• At 3 yrs, Kaplan-Meier estimated

cumulative % with events were 19.9% in

the no-T group vs. 25.7% in the T group.

No significant difference in the effect size

of T therapy among those with and

without CAD.

R. Vigen et al. JAMA 2013;310:1829-36

Survival Curves

R. Vigen et al. JAMA 2013;310:1829-36

Death by Testosterone?

We Think Not!




• Cohort study of risk of acute non-fatal MI

following an initial testosterone therapy

(TT) prescription (n = 55, 593). Evaluated

the incidence rate of MI in 90 days

following the initial prescription (post-

prescription interval) with rate one year

prior to prescription (pre-prescription

interval) compared to PDE5 inhibitors.

WD Finkle, et al. PLOS ONE, Jan 2014, Vol 9, Issue 1 e85805



• Results: post/pre-prescription rate ratio (RR) for

TT prescription was 1.36; Men aged ≥ 65 RR was

2.19 for TT pts and 1.15 for PDE5 I, RR for TT

prescriptions increased with age (0.95 for men <

55 yrs to 3.43 for pts ≥ 75 yrs). In men< 65 yrs,

excess risk was confined to those with a prior

history of heart disease,

• Conclusion: “In older men and in younger men

with pre-existing diagnosed heart disease, the risk

of MI following an initial TT prescription is

substantially increased.”WD Finkle, et al. PLOS ONE, Jan 2014, Vol 9, Issue 1 e85805

BUT - - -


• Trials were very heterogeneous and might

not be suitable for integration. Heterogeneity

in age, inclusion and exclusion criteria, study

duration, formulation, dose, baseline CV risk

• Broad outcome definition. Composite

outcome included more than 20 categories

including bleeding esophageal varices,

pericarditis, peripheral edema, aortic

aneurysms, hypotension, syncope, to death

from MI, giving each equal merit.

BUT - - -


• Not clear that all studies had full adverse

event reporting. Reported incidence of

cardiovascular-related events ranged from

<1% to 45%.

• Few of the articles in the meta-analysis pre-

specified CV safety outcomes or verified

these events by hospital records.

• Excluded trials of < 12 weeks duration but

did not specify how many

BUT - - -


• Many used were pilot studies or

studies with small n values

• Majority of studies did not specify

whether assessor of CV events

was blinded to treatment.

There are Also Studies in the Literature

Showing Just the Opposite

That Testosterone Reduces CV

Events and Mortality:


Shores MM, et al.Testosterone Treatment and Mortality in Med with Low Testosterone Levels.

J Clin Endocrinol Metab 2012;97: 2050

Limitations to These Studies as Well

For Example:

Shores study. Limitations pointed out by the authors:

• Observational study. Subjects treated in a clinical setting; not randomized to treatment

• Not adequately controlled for baseline factors. For example, physicians might have selected healthier men for T treatment. Unmeasured cofounders might exist.

• Entry into the study based on a single low level of T.

Limitations to These Studies as Well

For Example:

• Did not ascertain symptoms of low T

required to make the diagnosis of

hypogonadism.

• Total T rather than free T was

measured. T levels not obtained at a

standardized time.

• Cohort had a high degree of chronic

medical morbidity.

Risk of Myocardial Infarction in Older

Men Receiving Testosterone Therapy

• Using a 5% national sample of Medicare pts, authors identified 6355 pts treated with at least one injection of testosterone (T) between 1/1/1997 and 12/31/2005, and matched this cohort to 19,065 T non-users.

Baillargeon J, et al. Ann Pharmocother, DOI: 1060028014539918

Risk of Myocardial Infarction in Older

Men Receiving Testosterone Therapy

• Results: T therapy was not associated with

increased risk of MI (HR=0.85; 95% CI = 0.6-

1.02). In men at high risk of MI, T therapy

was associated with a reduced risk of MI

(HR=0.69; 95% CI = 0.53-0.92). No difference

in risk for lower pts at lower risk.

• Conclusions: Older men treated with IM T

did not have increased risk of MI. T was

moderately protective against MI in men

with high MI risk.Baillargeon J, et al. Ann Pharmocother, DOI: 1060028014539918

Limitations:

• Info on outcomes and risk factors came from

diagnostic codes, which might not be

accurate or complete.

• Medicare claims during study period provided

no data on other formulations.

• Did not assess other meds associated with

reduced MI (statins, antihypertensives)

• Data on pharmaceutical agents purchased

outside the plan were not captured

• Baseline T levels were not available

Thus the literature on whether exogenous testosterone is associated with CV events such as MI has mixed results. There is a need for a large, prospective, randomized, placebo-controlled, double-blinded,long-term study (~4-5 yrs), in which T or placebo is given to symptomatic hypogonadal men and the primary outcome is well defined cardiovascular events. These patients should have baseline T measurements, and T levels should be checked throughout the study.

The TIMES 2 StudyTestosterone Replacement in Hypogonadal Men

with Type 2 Diabetes

and/or Metabolic Syndrome

• This study tested the efficacy, safety, and

tolerability of transdermal 2%

testosterone gel over 12 mos. In 220

hypogonadal men with Type 2 diabetes

and/or metabolic syndrome in men ≥ 40

years. Avg age = 60 years.

• Testosterone therapy reduced insulin

resistance by 15.2% at 6 months (p=0.018)

and 16.4% at 12 mos (p=0.006).Jones TH et. al. Diabetes Care 2011; 34:828-837.

The TIMES 2 Study (cont’d)

• Testosterone therapy improved glycemic

control in Type 2 diabetes (Hbg AIC –

0.446%; p=0.035).

• Testosterone (T) improved total

cholesterol (4.77 control vs 4.49 T in

mmol/L at 12 mos) and improved LDL

cholesterol (2.75 C vs 2.59 T).

• Testosterone improved IIEF score, sexual

desire scores, and intercourse

satisfaction scores at 12 mos.

Jones TH et. al. Diabetes Care 2011; 34:828-837

The TIMES 2 Study (cont’d)

• Cardiovascular events occurred more commonly with placebo (10.7 vs 4.6%, p=0.095).

• Conclusion: Transdermal testosterone replacement therapy was associated with beneficial effects on insulin resistance, total, and LDL cholesterol, and sexual health in hypogonadal men with Type 2 Diabetes and/or metabolic syndrome.

Testosterone therapy was not associated with an increase CV events or other adverse events.

Jones TH et. al. Diabetes Care 2011; 34:828-837

Mean Percent Change From Baseline

Jones TH et al. Diabetes Care 2011;34:828-37.

CHF, chronic heart failure; HOMA-IR, homeostatic model assessment of insulin resistance. 1. Aukrust P et al. J Am Coll Cardiol. 2009;54(10):928-929. 2. Caminiti G et al. J Am Coll Cardiol. 2009;54(10):919-927.

CHF and Testosterone Therapy

• Heart failure complex, multistep disease1

– Disrupted endocrine and metabolic

systems

– Impaired exercise capacity and fatigue

– Associated low testosterone levels

• 25% of men with CHF have

hypogonadism

• Role in insulin resistance and loss of

muscle strength


• Effect of testosterone therapy for elderly

patients with CHF2

– Randomized, double-blind, placebo-

controlled study; N=64; mean age, 70 y

– Long-acting intramuscular testosterone

therapy at doses equivalent to those for

hypogonadism treatment

– Well-tolerated and, over 12 wk, improved

functional exercise capacity, muscle strength,

insulin sensitivity, and baroreflex sensitivity

CHF, chronic heart failure; HOMA-IR, homeostatic model assessment of insulin resistance. 1. Aukrust P et al.

J Am Coll Cardiol. 2009;54(10):928-929. 2. Caminiti G et al. J Am Coll Cardiol. 2009;54(10):919-927.

CHF, chronic heart failure; HOMA-IR, homeostatic model assessment o919-927. 3.5;90(7):3989-3994.


• Effect of testosterone therapy on insulin

resistance in men with moderately severe

CHF3

– Single-blind, placebo-controlled,

crossover study; N=13; mean age, 74 y

– Improved insulin sensitivity as

measured by HOMA-IR, accompanied by

increased total body mass and reduced

fat mass


• Testosterone treatment may cause

fluid retention, which can

contribute to CHF4

• Potential to treat CHF with

testosterone therapy1-3

–Larger studies and longer follow-

up needed

–Benefits vs risks

CHF, chronic heart failure; HOMA-IR, homeostatic model assessment o919-927. 3.5;90(7):3989-3994.

Summary

Low testosterone (T) levels are associated

with increased atherosclerosis.

Most early meta analyses showed that

administration of testosterone to men has

neutral effect on CV risk factors and

cardiac events.

However, current evidence about the

safety of testosterone treatment in men is

hampered by brief study follow-up and

sometimes soft end points.

Summary (cont’d)

While the TOM trial suggested possible increased CV risks of T therapy in elderly and frail individuals, caution is warranted in interpreting and extrapolating from the TOM trial findings to other doses and formulations of testosterone or to other populations, particularly men with hypogonadism without CVD or mobility limitations.

Serious limitations of recent JAMA, Plos One, and BMC Medical studies as pointed out by numerous investigators as well as the FDA. No black box warning for now regarding MI, stroke or death.

Summary (cont’d)

Recent studies by Shore, Muraleedharan,

and Baillarageon did not observe an increase

in mortality or MI rates with T (in fact,

suggest a protective effect).

In TIMES 2 testosterone treatment improved

insulin resistance, total and LDL cholesterol ,

sexual health in men with type 2 diabetes

and/or metabolic syndrome and was

associated with a nonsignificant trend

toward fewer cardiac events.

Summary (cont’d)

Clearly the issue of testosterone and C V

safety is an area that will need more long-

term study with hard CV endpoints.

When you see men with hypogonadism,

especially those with ED there could be

an increased risk of atherosclerosis – so

they should be evaluated for CV risk

factors and treated appropriately.

Corona G et al. Expert Opin Drug Saf, published online August 19,

2014

Mean Difference or Standardized Mean Difference

in Several Clinical Parameters after Testosterone Supplementation

as Derived from Meta-Analysis of the Available Evidence

Exercise duration Time to 1 mm ST depression Exercise capacity Peak in VO2

(mean difference; seconds) (mean difference; seconds) (standardized difference) (standardized

difference)

Stable CVD 168 (80.1; 255.9) 57.4 (9.9; 109.4)

HF 0.33 (0.003; 0.656) 1.23 (0.14; 2.32)

All p < 0.0001.

Adapted from [20,24].

CVD: Cardiovascular disease; HF: Heart

failure.

Comparisons on Available Meta-Analyses Evaluating the Relationship

between Testosterone Supplementation and CV Events

Calof et al. Haddad et al. Fernández-Balsells et al. Xu et al.

(2005) [25] (2007) [26] (2010) [27] (2013) [28]

Number of trials included 19 6 51 27

Number of patients analyzed 1084 308 2679 2944

Inclusion criteria Yes No Yes No Yes No Yes No

Time restriction (> 12 weeks) X X X X

Age restriction (≥ 45 years old) X X X X

All available RCTs reporting X X X X

CV adverse events

CV analysis

All CV events X X X X

Serious adverse events X X X X

(including MACE)

MACE X X X X

AMI X X X X

Acute coronary syndrome X X X X

Coronary by-pass surgery X X X X

Stroke X X X X

New heart failure X X X X

Arrhythmias X X X X

CV mortality X X X X

AMI: Acute myocardial infarction; CV: Cardiovascular; MACE: Major adverse cardiovascular events; RCTs: Randomized

controlled trials.

Corona G et al. Expert Opin Drug Saf, published online August 19, 2014

Trial Flow Diagram

Records identified through

different sources n = 2747

Records removed: No clinical trials n = 2287No human species n = 2No english language n = 13No male subsjects n = 145

Full-text articles assessed for eligibility n = 300

Full-text articles excluded: Women n = 4No T use included n = 45No RCT n = 21No placebo (or p-only) arm n = 108No T-only arm n = 4Study duplicates n = 18

Studies included in qualitative synthesis n = 101

Studies included in quantitative synthesis (meta-analysis) n = 75

Studies excluded (see table 6) n = 26

UNPUBLISHED Studies n = 649

Ongoing n = 202

No results available n = 372

No placebo n = 26

Women n = 21

No T arm n = 27

Study assessed for eligibility n = 1

RCT: Randomized clinical

trials;

T: Testosterone.

Corona G et al. Expert Opin Drug Saf, published online August 19,

2014

LL: Lower limit; MH-OR: Mantel-Haenszel odds ratio; UL: Upper

limit

Odds Ratio for Major Adverse Cardiovascular Events (MACE) in Subjects

Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure


TRT Placebo

0.01 0.1 1 10 100

Odds ratio for MACE

Placebo TS

Source MH - OR LL #Events # Patients #Events # Patients

Copenhagen SG, 1986 (31) 1,97 0,08 48,82 0,68Hall et al., 1996 (34) 0,32 0,01 8,23 0,49Sih et al., 1997 (36) 0,88 0,05 15,33 0,93Snyder et al., 1999 (40) 2,04 0,18 23,17 0,57English et al., 2000 (42) 3,12 0,12 80,39 0,49Seidman et al., 2001 (47) 0,41 0,02 10,83 0,59Steidle et al., 2003 (52) 2,83 0,11 70,27 0,53Armory et al., 2004 (54) 3,13 0,12 80,68 0,49Kenn et al., 2004 (56) 0,23 0,01 7,05 0,40Svartberg et al., 2004 (60) 0,29 0,01 7,74 0,46Brockenbrough et al., 2006 (63) 3,75 0,36 39,59 0,27Malkin et al., 2006 (69) 2,17 0,19 25,01 0,53Nair et al., 2006 (72) 5,70 0,26 123,78 0,27Svartberg et al., 2008 (81) 3,16 0,12 82,64 0,49Chapman et al., 2009 (84) 1,00 0,05 20,83 1,00Legros et al., 2009 (85) 1,01 0,04 25,01 1,00Aversa et al., 2010 (89) 0,08 0,00 2,07 0,13Aversa et al., 2010 (90) 0,07 0,00 1,97 0,12Basaria et al., 2010 (11) 13,39 0,74 240,78 0,08Kalinchenko et al., 2010 (92) 0,21 0,01 5,15 0,34Srinivas- Shankar et al., 2010 (93) 1,01 0,14 7,31 0,99Ho et al., 2011 (95) 1,00 0,06 16,37 1,00Jones et al., 2011 (96) 0,51 0,05 5,75 0,59Kaufman et al. 2011 (97) 0,87 0,04 18,48 0,93Behre et al. 2012 (99) 2,95 0,12 72,91 0,51 Hildreth et al. 2013 (100) 0,15 0,02 1,53 0,11 Overall 1,01 0,57 1,77 0,96

1 134 0 870 35 1 351 17 1 152 54 1 541 25 0 250 13 1 171 106 0 991 24 0 240 6 1 50 15 1 143 19 1 212 37 1 392 30 0 321 19 0 191 6 1 61 237 0 790 40 1 100 42 1 106 106 0 1030 113 1 712 136 2 1381 60 1 601 108 2 1122 234 0 401 183 0 1791 96 3 47

31 1895 20 1341

UL p

LL: Lower limit; MACE: Major adverse cardiovascular events; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit

Odds Ratio for Acute Myocardial Infarction (AMI), Acute Coronary Syndrome, Stroke, Heart

Failure, and Cardiovascular (CV) Mortality in Subjects Treated with Testosterone or Placebo

Odds ratio for MACE

Source # TrialsTRT Placebo

#Events # Patients #Events # Patients

Placebo TS

AMI 14 0,68 0,30 1,52 0,34

Acute coronary syndrome 15 0,92 0,43 1,97 0,83

Stroke 5 0,82 0,24 2,83 0,76

New heart failure 3 1,64 0,25 10,63 0,60

CV mortality 13 1,14 0,49 2,66 0,76

11 1086 11 747

18 1093 11 738

3 244 4 242

3 387 0 193

11 1173 8 928

pLL UL 0.01 0.1 1 10 100 MH-OR


CVD: Cardiovascular diseases; LL: Lower limit; UL: Upper

limit;

MH-OR: Mantel-Haenszel odds ratio; TT: Total testosterone

100

Odds ratio for MACESource # Trials MH-OR LL p TRT Placebo


Placebo TS

Associated diseases

Elderly men 10 1,22 0,49 3,03 0,67

Men with CVD 2 2,48 0,35 17,45 0,36

Frail men 5 2,25 0,72 7,08 0,17

Men with metabolic diseases 4 0,19 0,04 0,85 0,03

Hypogonadism status

Mixed population 14 1,26 0,58 2,73 0,56

TT < 12 nM 12 0,84 0,32 2,23 0,73

Type of support

Drug company not supported 12 0,94 0,39 2,24 0,88

Drug company supported 14 1,07 0,51 2,24 0,86

Trial duration

≤ 12 weeks 4 1,02 0,20 5,29 0,98

>12 weeks 22 1,01 0,55 1,84 0,98

13 954 6 549

3 62 1 64

13 401 4 355

1 303 5 203

15 1066 11 865

16 829 9 476

10 437 8 332

21 1458 12

2 147 2 145

29 1746 18 1196

0.01 0.1 1 10 UL

1009


Odds Ratio for Major Adverse Cardiovascular Events (MACE) According

to Baseline Characteristics in Subjects Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure

LL: Lower limit; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit

0.01 0.1 1 10 100

Odds ratio for overall CV events

Placebo TS

Copenhagen SG, 1986 (31) 2,22 0,78 6,31 0,13

Hall et al., 1996 (34) 0,19 0,01 4,08 0,29

Sih et al., 1997 (36) 0,88 0,05 15,33 0,93

Snyder et al., 1999 (40) 1,96 0,61 6,29 0,26

English et al., 2000 (42) 5,43 0,25 118,96 0,28

Seidman et al., 2001 (47) 0,41 0,02 10,83 0,59

Steidle et al., 2003 (52) 4,76 0,23 100,40 0,32

Amory et al., 2004 (54) 5,44 0,25 119,63 0,28

Kenny et al., 2004 (56) 0,23 0,01 7,05 0,40

Svartberg et al., 2004 (60) 0,29 0,01 7,74 0,46

Brockenbrough et al., 2006 (62) 1,20 0,34 4,18 0,77

Malkin et al., 2006 (69) 0,86 0,24 3,10 0,82

Merza et al., 2006 (71) 0,30 0,01 7,85 0,47

Nair et al., 2006 (72) 1,32 0,39 4,50 0,66

Okun et al., 2006 (73) 0,46 0,04 5,75 0,55

Emmelot-Vonk et al., 2008 (72) 2,35 0,59 9,33 0,22

Svartberg et al., 2008 (81) 3,16 0,12 82,64 0,49

Caminiti et al., 2009 (82) 2,06 0,18 23,83 0,56

Chapman et al., 2009 (84) 1,00 0,05 20,83 1,00

Legros et al., 2009 (85) 1,01 0,04 25,01 1,00

Aversa et al., 2010 (88) 0,08 0,00 2,07 0,13

Aversa et al., 2010 (90) 0,07 0,00 1,97 0,12

Basaria et al., 2010 (11) 6,05 2,22 16,51 0,00

Kalinchenko 2010 (91) 0,12 0,01 2,59 0,18

Srinivas-Shankar et al., 2010 (93) 2,60 0,49 13,61 0,26

Ho et al., 2011 (95) 1,00 0,14 7,34 1,00

Jones et al., 2011 (96) 0,40 0,14 1,19 0,10

Kaufman et al., 2011 (97) 1,49 0,33 6,71 0,60

Hoyos et al., 2012 (98) 3,18 0,13 81,01 0,48

Hildreth et al., 2013 (101) 0,14 0,04 0,48 0,00

NCT00957528 0,88 0,05 16,74 0,93

Overall 1,07 0,69 1,65 0,76

Source MH-OR p

16 134 5 87

0 35 2 35

1 17 1 15

9 54 5 54

2 25 0 25

0 13 1 17

2 106 0 99

2 24 0 24

0 6 1 5

0 15 1 14

9 19 9 21

5 37 6 39

0 20 1 19

7 30 6 32

1 15 2 15

7 120 3 117

1 19 0 19

2 35 1 35

1 6 0 6

1 237 0 79

0 40 1 10

0 42 1 10

25 106 5 103

0 113 2 71

5 136 2 138

2 60 2 60

5 108 12 112

17 234 2 40

1 33 0 34

4 96 11 47

1 9 1 8

126 1944 83 1390

TRT Placebo #Events # Patients #Events # Patients LL UL


Odds Ratio for Overall Cardiovascular Events in Subjects Treated with

Testosterone or Placebo


Mean Difference or Standardized Mean Difference

in Several Clinical Parameters after Testosterone Supplementation

as Derived from Meta-Analysis of the Available Evidence

Exercise duration Time to 1 mm ST depression Exercise capacity Peak in VO2

(mean difference; seconds) (mean difference; seconds) (standardized difference) (standardized

difference)

Stable CVD 168 (80.1; 255.9) 57.4 (9.9; 109.4)

HF 0.33 (0.003; 0.656) 1.23 (0.14; 2.32)

All p < 0.0001.

Adapted from [20,24].

CVD: Cardiovascular disease; HF: Heart

failure.

Comparisons on Available Meta-Analyses Evaluating the Relationship

between Testosterone Supplementation and CV Events


Calof et al. Haddad et al. Fernández-Balsells et al. Xu et al.

(2005) [25] (2007) [26] (2010) [27] (2013) [28]

Number of trials included 19 6 51 27

Number of patients analyzed 1084 308 2679 2944

Inclusion criteria Yes No Yes No Yes No Yes No

Time restriction (> 12 weeks) X X X X

Age restriction (≥ 45 years old) X X X X

All available RCTs reporting X X X X

CV adverse events

CV analysis

All CV events X X X X

Serious adverse events X X X X

(including MACE)

MACE X X X X

AMI X X X X

Acute coronary syndrome X X X X

Coronary by-pass surgery X X X X

Stroke X X X X

New heart failure X X X X

Arrhythmias X X X X

CV mortality X X X X

AMI: Acute myocardial infarction; CV: Cardiovascular; MACE: Major adverse cardiovascular events; RCTs: Randomized

controlled trials.

Trial Flow Diagram

Records identified through

different sources n = 2747

Records removed:

No clinical trials n = 2287

No human species n = 2

No english language n = 13

No male subsjects n = 145

Full-text articles assessed for eligibility n = 300

Full-text articles excluded:

Women n = 4

No T use included n = 45

No RCT n = 21

No placebo (or p-only) arm n = 108

No T-only arm n = 4

Study duplicates n = 18

Studies included in qualitative synthesis n = 101

Studies included in quantitative synthesis (meta-analysis) n = 75

Studies excluded (see table 6) n = 26

UNPUBLISHED Studies n = 649

Ongoing n = 202

No results available n = 372

No placebo n = 26

Women n = 21

No T arm n = 27

Study assessed for eligibility n = 1

RCT: Randomized clinical

trials; T: Testosterone.


LL: Lower limit; MH-OR: Mantel-Haenszel odds ratio; UL: Upper

limit

Odds Ratio for Major Adverse Cardiovascular Events (MACE) in Subjects

Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure


TRT Placebo

Source MH - OR LL #Events # Patients #Events # Patients

Copenhagen SG, 1986 (31) 1,97 0,08 48,82 0,68Hall et al., 1996 (34) 0,32 0,01 8,23 0,49Sih et al., 1997 (36) 0,88 0,05 15,33 0,93Snyder et al., 1999 (40) 2,04 0,18 23,17 0,57English et al., 2000 (42) 3,12 0,12 80,39 0,49Seidman et al., 2001 (47) 0,41 0,02 10,83 0,59Steidle et al., 2003 (52) 2,83 0,11 70,27 0,53Armory et al., 2004 (54) 3,13 0,12 80,68 0,49Kenn et al., 2004 (56) 0,23 0,01 7,05 0,40Svartberg et al., 2004 (60) 0,29 0,01 7,74 0,46Brockenbrough et al., 2006 (63) 3,75 0,36 39,59 0,27Malkin et al., 2006 (69) 2,17 0,19 25,01 0,53Nair et al., 2006 (72) 5,70 0,26 123,78 0,27Svartberg et al., 2008 (81) 3,16 0,12 82,64 0,49Chapman et al., 2009 (84) 1,00 0,05 20,83 1,00Legros et al., 2009 (85) 1,01 0,04 25,01 1,00Aversa et al., 2010 (89) 0,08 0,00 2,07 0,13Aversa et al., 2010 (90) 0,07 0,00 1,97 0,12Basaria et al., 2010 (11) 13,39 0,74 240,78 0,08Kalinchenko et al., 2010 (92) 0,21 0,01 5,15 0,34Srinivas- Shankar et al., 2010 (93) 1,01 0,14 7,31 0,99Ho et al., 2011 (95) 1,00 0,06 16,37 1,00Jones et al., 2011 (96) 0,51 0,05 5,75 0,59Kaufman et al. 2011 (97) 0,87 0,04 18,48 0,93Behre et al. 2012 (99) 2,95 0,12 72,91 0,51 Hildreth et al. 2013 (100) 0,15 0,02 1,53 0,11 Overall 1,01 0,57 1,77 0,96

1 134 0 870 35 1 351 17 1 152 54 1 541 25 0 250 13 1 171 106 0 991 24 0 240 6 1 50 15 1 143 19 1 212 37 1 392 30 0 321 19 0 191 6 1 61 237 0 790 40 1 100 42 1 106 106 0 1030 113 1 712 136 2 1381 60 1 601 108 2 1122 234 0 401 183 0 1791 96 3 47

31 1895 20 1341

UL p 0.01 0.1 1 10 100

Odds ratio for MACE

Placebo TS

LL: Lower limit; MACE: Major adverse cardiovascular events; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit

Odds Ratio for Acute Myocardial Infarction (AMI), Acute Coronary Syndrome,

Stroke, Heart Failure, and Cardiovascular (CV) Mortality

in Subjects Treated with Testosterone or Placebo


Odds ratio for

MACESource # TrialsTRT Placebo


Placebo TS

AMI 14 0,68 0,30 1,52 0,34

Acute coronary syndrome 15 0,92 0,43 1,97 0,83

Stroke 5 0,82 0,24 2,83 0,76

New heart failure 3 1,64 0,25 10,63 0,60

CV mortality 13 1,14 0,49 2,66 0,76

11 1086 11 747

18 1093 11 738

3 244 4 242

3 387 0 193

11 1173 8 928

pLL UL 0.01 0.1 1 10 100 MH-OR

CVD: Cardiovascular diseases; LL: Lower limit; UL: Upper limit;

MH-OR: Mantel-Haenszel odds ratio; TT: Total testosterone


Odds Ratio for Major Adverse Cardiovascular Events (MACE) According

to Baseline Characteristics in Subjects Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure

Source # Trials MH-OR LL p TRT Placebo#Events # Patients #Events # Patients

Associated diseases

Elderly men 10 1,22 0,49 3,03 0,67

Men with CVD 2 2,48 0,35 17,45 0,36

Frail men 5 2,25 0,72 7,08 0,17

Men with metabolic diseases 4 0,19 0,04 0,85 0,03

Hypogonadism status

Mixed population 14 1,26 0,58 2,73 0,56

TT < 12 nM 12 0,84 0,32 2,23 0,73

Type of support

Drug company not supported 12 0,94 0,39 2,24 0,88

Drug company supported 14 1,07 0,51 2,24 0,86

Trial duration

≤ 12 weeks 4 1,02 0,20 5,29 0,98

>12 weeks 22 1,01 0,55 1,84 0,98

13 954 6 549

3 62 1 64

13 401 4 355

1 303 5 203

15 1066 11 865

16 829 9 476

10 437 8 332

21 1458 12

2 147 2 145

29 1746 18 1196

UL

1009

100

Odds ratio for

MACE

Placebo TS

0.01 0.1 1 10 0.01 0.1 1 10 100

LL: Lower limit; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit


Odds Ratio for Overall Cardiovascular Events in Subjects Treated with

Testosterone or Placebo

16 134 5 87

0 35 2 35

1 17 1 15

9 54 5 54

2 25 0 25

0 13 1 17

2 106 0 99

2 24 0 24

0 6 1 5

0 15 1 14

9 19 9 21

5 37 6 39

0 20 1 19

7 30 6 32

1 15 2 15

7 120 3 117

1 19 0 19

2 35 1 35

1 6 0 6

1 237 0 79

0 40 1 10

0 42 1 10

25 106 5 103

0 113 2 71

5 136 2 138

2 60 2 60

5 108 12 112

17 234 2 40

1 33 0 34

4 96 11 47

1 9 1 8

126 1944 83 1390

TRT Placebo #Events # Patients #Events # Patients

Copenhagen SG , 1986 (31) 2,22 0,78 6,31 0,13

Hall et al., 1996 (34) 0,19 0,01 4,08 0,29

Sih et al., 1997 (36) 0,88 0,05 15,33 0,93

Snyder et al., 1999 (40) 1,96 0,61 6,29 0,26

English et al., 2000 (42) 5,43 0,25 118,96 0,28

Seidman et al., 2001 (47) 0,41 0,02 10,83 0,59

Steidle et al., 2003 (52) 4,76 0,23 100,40 0,32

Amory et al., 2004 (54) 5,44 0,25 119,63 0,28

Kenny et al., 2004 (56) 0,23 0,01 7,05 0,40

Svartberg et al., 2004 (60) 0,29 0,01 7,74 0,46

Brockenbrough et al., 2006 (62) 1,20 0,34 4,18 0,77

Malkin et al., 2006 (69) 0,86 0,24 3,10 0,82

Merza et al., 2006 (71) 0,30 0,01 7,85 0,47

Nair et al., 2006 (72) 1,32 0,39 4,50 0,66

Okun et al., 2006 (73) 0,46 0,04 5,75 0,55

Emmelot-Vonk et al., 2008 (72) 2,35 0,59 9,33 0,22

Svartberg et al., 2008 (81) 3,16 0,12 82,64 0,49

Caminiti et al., 2009 (82) 2,06 0,18 23,83 0,56

Chapman et al., 2009 (84) 1,00 0,05 20,83 1,00

Legros et al., 2009 (85) 1,01 0,04 25,01 1,00

Aversa et al., 2010 (88) 0,08 0,00 2,07 0,13

Aversa et al., 2010 (90) 0,07 0,00 1,97 0,12

Basaria et al., 2010 (11) 6,05 2,22 16,51 0,00

Kalinchenko 2010 (91) 0,12 0,01 2,59 0,18

Srinivas-Shankar et al., 2010 (93) 2,60 0,49 13,61 0,26

Ho et al., 2011 (95) 1,00 0,14 7,34 1,00

Jones et al., 2011 (96) 0,40 0,14 1,19 0,10

Kaufman et al., 2011 (97) 1,49 0,33 6,71 0,60

Hoyos et al., 2012 (98) 3,18 0,13 81,01 0,48

Hildreth et al., 2013 (101) 0,14 0,04 0,48 0,00

NCT00957528 0,88 0,05 16,74 0,93

Overall 1,07 0,69 1,65 0,76

Source MH-OR pLL UL 0.01 0.1 1 10 100

Odds ratio for overall CV events

Placebo TS

hypogonadism: controversies of diagnosis and treatmentcontroversies) late onset...

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