Feb., 2014 mens urological health cme testosterone replacement -

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CLINICAL PRACTICE Q&A A CME PROGRAM FOR MEN’S UROLOGICAL HEALTH

LOW TESTOSTERONE

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STEERING COMMITTEE

Lydia Hatcher, MD, CCFP, FCFP Clinical Associate, Professor of Family Medicine, Memorial University of Newfoundland

Jay Lee, MD, FRCSC Clinical Assistant Professor, Division of Urology, Department of Surgery, University of Calgary

Ghalib Ahmed, MD, CCFP General Family Practitioner, Associate Clinical Professor, Department of Family Practice, University of Alberta

Stacy Elliott, MD Director, BC Center for Sexual Medicine, Sexual Medicine Consultant, Men’s Health Initiative, Vancouver Coastal Health Clinical Professor, Departments of Psychiatry and Urologic Sciences, University of British Columbia

Serge Carrier, MD, FRCSC Associate Professor, Division of Urology, Department of Surgery, McGill University

Murray Awde, MD, CCFP, FCFP Clinical Professor of Family Medicine, University of Western Ontario

Anthony Bella, MD, FRCSC Greta and John Hansen Chair in Men's Health Research, Assistant Professor of Urology, Department of Surgery, Associate Scientist, Neuroscience, University of Ottawa

Gerald Brock, MD, FRCSC Professor of Surgery, Urology Program Director, University of Western Ontario Chair, Office of Education, Canadian Urology Association

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STEERING COMMITTEE DISCLOSURES

Ghalib Ahmed, MD, CCFP • Grants/Research Support: AstraZeneca, Bristol-Myers Squibb,

Pfizer, Servier, Sunovion • Speaker’s Bureau/Honoraria: Abbott, AstraZeneca, Eli Lilly,

Lundbeck, Merck, Pfizer, Shire • Consulting Fees: Abbott, AstraZeneca, Bayer, Boehringer

Ingelheim, Bristol-Myers Squibb, Eli Lilly, Lundbeck, Merck, Pfizer

Murray Awde, MD, CCFP, FCFP • Grants/Research Support: Astellas, Bristol-Myers Squibb,

Boehringer Ingelheim, Merck, Novartis, Otsuka, Purdue Pharmaceuticals

• Speaker’s Bureau/Honoraria: Abbott, AstraZeneca, Bayer, LEO, Takeda, Nycomed

• Consulting Fees: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer

Anthony Bella, MD, FRCSC • Grants/Research Support: Acorda Therapeutics, Canadian

Foundation for Innovation, Canadian Male Sexual Health Council, Northeastern Section American Urological Association

• Speaker’s Bureau/Honoraria: Abbott, American Medical Systems, Bayer, Coloplast, Eli Lilly, Pfizer

Gerald Brock, MD, FRCSC • Grants/Research Support: American Medical Systems, Eli Lilly,

GlaxoSmithKline, Pfizer • Speaker’s Bureau/Honoraria: American Medical Systems, Bayer,

Coloplast, Eli Lilly, GlaxoSmithKline, Pfizer • Consulting Fees: Bayer, Eli Lilly, GlaxoSmithKline, Pfizer

Serge Carrier, MD, FRCSC • Grants/Research Support: Bayer, Eli Lilly, Pfizer • Speaker’s Bureau/Honoraria: Abbott, Bayer, Eli Lilly, Pfizer

Stacy Elliott, MD • Speaker’s Bureau/Honoraria: Abbott, Bayer, Eli Lilly, Pfizer • Consulting Fees: Abbott, Bayer, Eli Lilly, Pfizer

Lydia Hatcher, MD, CCFP, FCFP • Grants/Research Support: Servier • Speaker’s Bureau/Honoraria: AstraZeneca, Boehringer Ingelheim,

Eli Lilly, Janssen-Ortho, Merck, Nycomed, Pfizer, Purdue Pharmaceuticals, Takeda, Valeant

• Consulting Fees: AstraZeneca

Jay Lee MD, FRCSC • Speaker’s Bureau/Honoraria: Abbott, Bayer, Eli Lilly,

GlaxoSmithKline, Pfizer

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SPEAKER DISCLOSURES

• Faculty: [Speaker’s name]

• Grants/Research Support:

• Speaker’s Bureau/Honoraria:

• Consulting Fees:

• Other:

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DISCLOSURE OF COMMERCIAL SUPPORT

• This program has received financial support from Eli Lilly Canada Inc in the form of an educational grant

• This program has received in-kind support from Eli Lilly Canada Inc in the form of logistical support.

• Potential for conflict(s) of interest: • [Speaker/Faculty name] has received funding Eli Lilly Canada Inc.

• Eli Lilly markets testosterone solution, a product that will be discussed in this program.

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MITIGATING POTENTIAL BIAS

• All content in this presentation has been developed, reviewed and approved by the Steering Committee

• All the recommendations involving clinical medicine are based on evidence from well-designed clinical trials published in peer-reviewed journals

• All testosterone formulations currently available in Canada will be discussed in this CME event

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LOW TESTOSTERONE

How do I decide which agent to prescribe for

testosterone deficiency? 2

How should patients on testosterone therapy be

monitored? 3

If untreated, what are the consequences of testosterone

deficiency? 4

What are the risks associated with testosterone therapy? 5 Does testosterone therapy

impact comorbid conditions? 6

How do I diagnose testosterone deficiency? 1

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LOW TESTOSTERONE

How do I diagnose testosterone deficiency? 1

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LEARNING OBJECTIVES

• After addressing this question participants will be able to:

• Identify the assessments required for the diagnosis of testosterone deficiency and integrate these into clinical practice

• Evaluate the serum testosterone measurements and review the current testing recommendations

• Be able to differentiate primary and secondary causes of low testosterone

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HOW DO I DIAGNOSE TESTOSTERONE DEFICIENCY?

• Subjective testing

• Objective testing

1. Morales et al. CUAJ. 2010;4:269-75.

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SUBJECTIVE TESTING

• History and physical exam:1,2

• General health evaluation NO acute or subacute illness

• Assess signs and symptoms

• Sensitive screening questionnaires correlate symptoms with biochemically low testosterone (i.e. ADAM Questionnaire)3

• Evaluate patients for comorbid conditions and risk factors associated with low testosterone

ADAM: androgen deficiency in aging males. 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 3. Morley et al. Metabolism. 2000;49:1239-42.

Click here for more info on the ADAM Questionnaire

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SYMPTOMS OF TESTOSTERONE DEFICIENCY

1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

Mild

Severe

De

gre

e o

f D

efi

cie

ncy

• Decreased libido • Decreased vitality • Fatigue • Mood changes • Insomnia • Anemia • Delayed ejaculation • Flushes • Erectile dysfunction • Decreased muscle mass • Increased visceral body fat • Testicular atrophy • Weakness • Osteopenia/osteoporosis • Loss of facial, axillary and pubic hair

What symptoms are characteristic of

testosterone deficiency? Q

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LOW TESTOSTERONE HIGH-RISK GROUPS

• Type 2 diabetes

• Metabolic syndrome

• HIV-associated weight loss

• Treatment with opioids, glucocorticoids or ketoconazole

• Osteoporosis or low trauma fracture at a young age

• End-stage renal disease and maintenance hemodialysis

• Chronic obstructive pulmonary disease

• Infertility

• Sellar region mass, disease, radiation or trauma

• Use of street drugs

• Liver disease


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OBJECTIVE TESTING

• Serum testosterone measurement • Measure when signs and symptoms of testosterone deficiency are present:

• Low libido

• Sexual dysfunction

• Low energy

• Testosterone levels are thought to be influenced by circadian rhythm • Higher levels in the morning

• Measure between 7 a.m. and 11 a.m.1,2


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SERUM TESTOSTERONE

Alb: albumin; SHBG: sex hormone binding globulin; T: testosterone. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

Bioavailable

Free (0.5-3%)

Albumin Bound (~38%)

SHBG Bound (~60%)

Total

T

SHBG T

T Alb

SHBG T

SHBG T

SHBG T

SHBG T

SHBG T

T Alb

T Alb

T

Free

T

T Alb

T Alb

T Alb

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WHICH TESTOSTERONE MEASURE?

Which measure of serum testosterone should be used to diagnose

testosterone deficiency?

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COMPARING TESTOSTERONE MEASURES

SHBG: sex hormone binding globulin. 1. Rosner et al. J Clin Endocrin. 2007;92:405-13; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 3. Morales et al. CUAJ. 2010;4:269-75.

Free and bioavailable testosterone calculator: http://www.issam.ch/freetesto.htm

Pros1,3 Cons1,2

Total Testosterone

• Widely available • Simple, rapid, inexpensive • Minimal technical expertise

• Poor accuracy, sensitivity and between-laboratory comparability

• Interpretation greatly affected by alterations in SHBG

Free Testosterone

• Relatively accurate • Relatively sensitive and

reproducible

• Less frequently available • Relatively expensive • Technically cumbersome and

difficult

Bioavailable Testosterone

• Technically simple • Correlates well with

symptoms

• Less frequently available • Relatively expensive • Can be inaccurate due to

incomplete precipitation

Click for factors that influence SHBG

Click on the website for a screen shot of

the online tool.

http://www.issam.ch/freetesto.htm

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TESTING RECOMMENDATIONS

• Canadian consensus recommends bioavailable testosterone2,3

• Acceptable alternatives:

• Calculated free testosterone

• Calculated bioavailable testosterone

• Total testosterone

• The American Endocrine Society recommends total testosterone1 • Free or bioavailable testing should be considered in patients who are at the

lower end of normal

1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Morales et al. CUAJ. 2010;4:269-75; 3. Bebb. BCMJ. 2011;53:474-79.

What test do you use to determine testosterone level? Q

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QUANTIFYING TESTOSTERONE DEFICIENCY

1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

What value defines testosterone deficiency? Q

10.4 nmol/L

Average testosterone threshold. Patients below this have a greater

likelihood of symptoms1

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LOW TESTOSTERONE

• Low testosterone requires investigation of:1

• SHBG levels

• Serum luteinizing hormone

• Follicle-stimulating hormone

• Prolactin

• Distinguish between primary and secondary causes

SHBG: sex hormone binding globulin. 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

If testosterone level is borderline or low, repeat testing is required for confirmation1,2

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PRIMARY VS. SECONDARY CAUSES

Results in: •Low testosterone levels • Impairment of spermatogenesis •Elevated gonadotropin levels

Results in: •Low testosterone levels • Impairment of spermatogenesis •Low/low-normal gonadotropin levels

Primary causes • Testicular origin

Secondary causes • Pituitary/hypothalamic origin

Low serum testosterone

Exclude: •Klinefelter syndrome

Exclude: •Pituitary neoplasia •Hyperprolactinemia •Hemochromatosis •Obstructive sleep apnea •Genetic disorders associated with

gonadotropin deficiency


Click for comparative treatment algorithm

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LOW END OF NORMAL


How would you manage a patient with testosterone levels at the

low end of normal? Q

Initiate testosterone therapy if the patient is symptomatic, evaluate response

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DIFFERENTIAL DIAGNOSIS

• If testosterone levels are in the normal range, consider other conditions causing fatigue: • Depression

• Hypothyroidism

• Sexual dysfunction (low libido/ED) from other causes

• Osteoporosis

• Cardiovascular disease

• Metabolic syndrome

• Diabetes

• Anemia

What conditions present with features similar to testosterone deficiency? Q

ED: erectile dysfunction.

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TAKE HOME MESSAGES

• Diagnostic assessments of testosterone deficiency include: • Subjective testing: medical history, physical examination and assessment of

characteristic symptoms of low testosterone

• Objective testing: measure of serum testosterone levels

• The American Endocrine Society recommends total testosterone • Canadian consensus recommends measuring bioavailable testosterone

• Confirm any low or borderline testosterone results

• Primary and secondary causes can be distinguished through measurements of SHBG, LH, FSH and prolactin

FSH: follicle-stimulating hormone; LH: luteinizing hormone; SHBG: sex hormone binding globulin. 1. Morales et al. CUAJ. 2010;4:269-75.

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LOW TESTOSTERONE

How do I decide which agent to prescribe for

testosterone deficiency? 2

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LEARNING OBJECTIVES


• Assess the available formulations for the treatment of testosterone deficiency

• Identify the role of a newly approved testosterone formulation

• Evaluate factors that influence prescription decisions for treating testosterone deficiency

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HOW DO I DECIDE WHICH AGENT TO PRESCRIBE FOR TESTOSTERONE DEFICIENCY?


• Safety/tolerability • Efficacy • Patient preference • Cost/insurance coverage

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TESTOSTERONE FORMULATIONS IN CANADA

Testosterone Formulation Brand Name

Oral • Testosterone undecanoate

• Andriol • pms-Testosterone

Intramuscular injections • Testosterone cypionate • Testosterone enanthate

• Depo-testosterone • Delatestryl

Testosterone patch • Androderm

Testosterone topical solution • Axiron

Testosterone gel • Tube • Sachet/pump

• Testim • AndroGel

Click for info on the testosterone

pipeline

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CONTRAINDICATIONS TO TESTOSTERONE

AUA: American Urological Association; IPSS: international prostate symptom score; PSA: prostate specific antigen. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Morales et al. CUAJ. 2010;4:269-75.

Absolute Contraindications

• Prostate or breast cancer • Hematocrit >54%

Relative Contraindications

• Severe lower urinary tract symptoms (AUA/IPSS score >19) • Prostate nodule • Baseline PSA greater than 4 ng/mL, or PSA >3 ng/mL in men

at high risk of prostate cancer • Uncontrolled congestive heart failure • Myocardial infarction, acute coronary event, unstable

angina, or coronary revascularization procedure in the preceding 6 months

• Untreated severe obstructive sleep apnea

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ORAL TESTOSTERONE

*This dose should be taken for 2-3 weeks. Subsequent dosages may be reduced to 40-120 mg daily.

1. Andriol Product Monograph. Merck Canada Inc; 2. pms-Testosterone Product Monograph. Pharmascience Inc; 3. Morales et al. CUAJ. 2010;4:269-75; 4. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

Product Dosage

Testosterone undecanoate1,2

(Andriol, pms-Testosterone) 120-160 mg daily divided

in 2 doses*

• Pros3,4

• Convenient administration

• Cons3,4

• Taken with a high fat meal

• Absorption issues may lead to poor response

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ORAL TESTOSTERONE: SAFETY/EFFICACY CONSIDERATIONS

• Safety Considerations1

• No safety considerations specific to oral formulations

• Efficacy Considerations1,2

• Limited efficacy due to unreliable oral bioavailability, fluctuating serum levels and short half-life

• Requires multiple daily dosing

1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Nieschlag et al. Hum Reprod Update. 2004;10:409-19.

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ORAL TESTOSTERONE: SERUM TESTOSTERONE PROFILE

• T undecanoate should be taken with a normal meal or breakfast to achieve proper T levels

T: testosterone. 1. Andriol Product Monograph. Merck Canada Inc.

Time (hours)

Me

an T

Co

nce

ntr

atio

n

(ng

/mL)

― 80 mg Fed ― 80 mg Fasted

0

2

4

6

8

10

0 2 4 6 8 10 12 14 16 18 20 22 24

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• Pros3,4

• Relatively inexpensive

• Effective

• Long-acting

• Flexibility of dosing

INTRAMUSCULAR INJECTIONS

1. Depo-Testosterone Product Monograph. Pfizer Canada Inc; 2. Delatestryl Product Monograph. Valeant Canada LP; 3. Morales et al. CUAJ. 2010;4:269-75; 4. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

Product Dosage

Testosterone cypionate1

(Depo-Testosterone) 200 mg every 2 weeks

(max. dose 400 mg per month)

Testosterone enanthate2

(Delatestryl) 100-400 mg every 1-4 weeks

• Cons3,4

• Waning effect between injections

• Requires intramuscular injection

• Greatest risk of erythrocytosis

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INTRAMUSCULAR INJECTIONS: SAFETY/EFFICACY CONSIDERATIONS


• Pain at injection site

• Fluctuations in mood, energy and sexual desire

• Coughing episodes immediately after intramuscular injection

• Supraphysiologic levels can reduce HDL


• Serum testosterone levels rise into the supraphysiologic range within 24-48 hours

• Gradually decline into the hypogonadal range over the next 2 weeks

HDL: high-density lipoprotein. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Nieschlag et al. Hum Reprod Update. 2004;10:409-19.

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INTRAMUSCULAR INJECTIONS: SERUM TESTOSTERONE PROFILE

1. Behre et al. Testosterone: Action-Deficiency-Substitution. Cambridge; UK; 2004.

Testosterone enanthate

Time (days)

Test

ost

ero

ne

(n

g/d

L)

200 mg

0

200

400

600

800

1000

1200

1400

0 2 4 6 8 10 12 14 16 18 20

Testosterone cypionate

Time (days)

Test

ost

ero

ne

(n

g/d

L)

0

200

400

600

800

1000

1200

1400

― 200 mg

0 1 2–3 4–5 6–7 8–10 11–12 13–14

―

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TRANSDERMAL PATCH

1. Androderm Product Monograph. Watson Laboratories, Inc; 2. Morales et al. CUAJ. 2010;4:269-75; 3. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

Product Dosage

Transdermal Patch1

(Androderm) 2.5 or 5 mg patch applied daily

• Pros2,3

• Ease of application

• Cons2,3

• Visibility of product

• Significant skin reactions

• Serum testosterone may be low-normal

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TESTOSTERONE PATCH: SAFETY/EFFICACY CONSIDERATIONS


• Frequent skin reactions at the application site


• Serum testosterone in the mid-normal range 4-12 hours after application

• Some patients require two 5 mg patches to achieve target levels


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0

400

800

1200

1600

2000

0 6 12 18 24

Te

sto

ste

ron

e (

ng/

dL)

Time (hours)

TESTOSTERONE PATCH: SERUM TESTOSTERONE PROFILE

1. Dobs et al. J Clin Endocrinol Metab. 1999;84:3469-78.

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DIRECT COMPARISON OF TRANSDERMAL PATCH TO GELS

*Sixteen patients discontinued product due to skin irritation.

1. Wang C, et al. J Clin Endocrinol Metab. 2000;85:2839-53; 2. AndroGel Product Monograph. Abbott Laboratories Ltd; 3. Androderm Product Monograph. Watson Labs Inc.

Product Patients with

Skin Irritation1 Type of Irritation1

Gel: 50 mg/day testosterone (5 g, 1% testosterone USP)2

5.7% Erythema

Gel: 100 mg/day testosterone (10 g, 1% testosterone USP)2

5.3% Erythema

Patch: Testosterone transdermal delivery system (testosterone)3

65.8%* Mild erythema to

intense erythema with blisters

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TRANSDERMAL GELS

1. AndroGel Product Monograph. Abbott Laboratories Ltd; 2. Testim Product Monograph. Auxilium Pharmaceuticals, Inc; 3. Morales et al. CUAJ. 2010;4:269-75; 4. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

Product Concentration Dose Application Site

AndroGel sachet1

1% testosterone 1-2 sachets daily (50-100 mg daily)

Shoulders +/- abdomen

AndroGel pump1 1% testosterone 2-8 actuations daily (12.5 mg/actuation)


Testim2 1% testosterone 1-2 tubes daily (50-100 mg daily)


• Pros3,4

• Minimal side effects

• Ease of application

• Flexibility of dosing

• Cons3,4

• Risk of secondary exposure from gel transference

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TESTOSTERONE GEL: SAFETY/EFFICACY CONSIDERATIONS


• Potential risk of gel transfer to another person who might come in close contact

• Skin irritation at application site


• Raise serum total and free testosterone concentrations into the mid-normal range in hypogonadal men over 24 hours

• ̴25% of patients will require >5 g of testosterone gel to achieve target levels


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TESTOSTERONE GELS: SERUM TESTOSTERONE PROFILE

Short-term Long-term

Days Since Treatment Initiation

Seru

m T

(n

mo

l/L)

Time (hours)

90 120 150 180

0

10

20

30

40

0 30 60 900

10

20

30

40

0 8 16 24

― 50 mg testosterone (5 g, 1% AndroGel) ― 100 mg testosterone (10 g, 1% AndroGel)

T: testosterone. 1. Swerdloff et al. J Clin Endocrinol Metab. 2000;85:4500-10.

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TRANSDERMAL TOPICAL SOLUTION

• NOC in Canada March 30, 2012

Product Concentration Dose Application Site

Axiron 2% testosterone 2-4 actuations daily (60-120 mg daily)

Axilla

• Pros

• Ease of application (applied to axilla with applicator)

• Minimal side effects

• Flexible dosing

• Cons

• Risk of secondary exposure from transference

1. Axiron Product Monograph. Eli Lilly Canada Inc.

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TRANSDERMAL TOPICAL SOLUTION: METERED DOSING SYSTEM

• Testosterone topical solution is available as a metered-dose pump containing 110 mL of solution

• The pump is capable of dispensing 90 mL of solution in 60 metered pump actuations

• One pump actuation delivers 30 mg of testosterone in 1.5 mL of solution


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• Patient should apply deodorant before testosterone topical solution

TRANSDERMAL TOPICAL SOLUTION: DOSING AND ADMINISTRATION


Daily Prescribed Dose Each Application Requires 1 Depression of the Pump

30 mg Apply 1 application: • ONE axilla (left OR right)

60 mg Apply 2 applications: • ONE to both the left AND right axilla

90 mg Apply 3 applications: • ONE to both the left AND right axilla • Wait for the product to dry • Again apply to ONE axilla (left OR right)

120 mg Apply 4 applications: • ONE to both the left AND right axilla • Wait for the product to dry • Again apply to both the left AND right axilla

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TESTOSTERONE TOPICAL SOLUTION: SAFETY/EFFICACY CONSIDERATIONS


• Potential risk of skin-to-skin transfer of testosterone solution

• Skin irritation at application site


• Provides continuous dosing (over 24-hour period) to deliver physiological levels in the normal concentration range

• Steady-state serum concentrations are attained within approximately 1 week of daily dosing

• Patients should avoid swimming/showering for at least 2 hours


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0

200

400

600

800

1000

1200

1400

0 4 8 12 16 20 24

TRANSDERMAL TESTOSTERONE SOLUTION: SERUM TESTOSTERONE PROFILE

Time from Dose (hours)

Seru

m T

ota

l Tes

tost

ero

ne

Co

nce

ntr

atio

n (

ng

/dL)

Mean (± SD) steady-state serum testosterone concentrations on Day 120 (30, 60, 90 or 120 mg testosterone) in completers

Upper limit of normal

Lower limit of normal


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PRESCRIBING DECISIONS: PATIENT FACTORS

• Patient Preference: • Mode of delivery

• Frequency of administration

• Daily (patch, topical solution, gel, or oral)

• Bi-monthly (injectable testosterone cypionate and testosterone enanthate)

• Cost/Insurance Coverage

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TAKE HOME MESSAGES

• Several testosterone formulations are available in Canada: • Oral (testosterone undecanoate)

• Testosterone patch

• Testosterone topical solution (underarm applicator)

• Testosterone gel (tube, sachet/pump)

• Intramuscular injections (testosterone cypionate and testosterone enanthate)

• Selection should be based upon safety, tolerability, efficacy and patient preference


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LOW TESTOSTERONE

How should patients on testosterone therapy be monitored? 3

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LEARNING OBJECTIVES


• Identify and implement appropriate follow-up for a patient on testosterone therapy

• Assess the time-to-symptom improvement after initial treatment for major symptoms

• Recognize when referral to a specialist is required

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HOW SHOULD PATIENTS ON TESTOSTERONE THERAPY BE MONITORED?

DRE: digital rectal exam; PSA: prostate specific antigen. 1.Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

• If stable...

• 3-6 months in the first year • Every year thereafter

• Follow-up should include: • Symptom response • Change in blood parameters • Monitoring adverse events • PSA/DRE testing

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SYMPTOM IMPROVEMENT

BMD: bone mineral density; MetS: metabolic syndrome. 1. Morales et al. CUAJ. 2010;4:269-75.

Duration of Treatment (months)

Enhanced libido

Improved emotional well-being

Increased energy

Reduced ED

Increased strength

Enhanced BMD

Improved cognition

Enhanced cardiovascular strength

Decreased body fat

Improvement in some components of MetS

Sym

pto

m Im

pro

vem

en

t

0 12 6 3

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CHANGES IN BLOOD PARAMETERS

• Assess hematocrit levels1

• Testosterone therapy increases red cell mass in a dose-dependent manner2

• If hematocrit >54%, stop therapy until hematocrit decreases to safe levels

• Evaluate patient for hypoxia and sleep apnea

• Restart therapy — consider different testosterone formulation

• Assess serum testosterone levels1

• Testosterone therapy aims to raise levels to the mid-normal range

1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Coviello et al. J Clin Endocrinol Metab. 2008;93:914-19.

What would you do if hemoglobin levels are high? Q

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ADVERSE EVENTS

• Potential adverse events:1

• Acne, oiliness of skin

• Breast tenderness

• Erythrocytosis

• Growth of metastatic prostate cancer

• Detection of subclinical prostate cancer

• Reduced sperm production and infertility

• Leg edema and worsening of obstructive sleep apnea*

• Gynecomastia*

• Growth of breast cancer*

• Male pattern balding*

*Weak evidence of association. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70.

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FORMULATION-SPECIFIC FOLLOW-UP

1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Bebb. BCMJ. 2011;53:474-79; 3. Axiron Product Monograph. Eli Lilly Canada.

Adjust dose (and/or frequency) to obtain testosterone levels in the mid-normal range

Testosterone Therapy When To Measure Serum Testosterone: Evaluate Patient For:

Oral (Andriol, Pms-Testosterone)1,2

3-5 hours after ingestion • Compliance • Taken with fat, split doses

Testosterone patch (Androderm) 1,2

2-12 hours after application • Skin reactions

Testosterone topical solution (Axiron)3

Any time >1 week after initiation of topical solution

• Adherence to protocols which minimize transfer and maximize absorbance

Testosterone gel (Testim, AndroGel) 1,2

Any time >1 week after initiation of gel use — ideally 3-4 hours after application

• Adherence to protocols which minimize transfer and maximize absorbance

Intramuscular injections (Delatestryl, Depo-testosterone,)1,2

Midway between injections, or at trough

• Fluctuations in mood/libido • Cough after injections

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PSA/DRE TESTING

• Prostate health should be assessed by PSA/DRE

• Recommended for men >40 years with baseline PSA >0.6 ng/mL who are initiating testosterone

• PSA measurements should be obtained: • Before treatment

• 3-6 months after treatment initiation

• In accordance with guidelines for prostate cancer screening

DRE: digital rectal exam; PSA: prostate specific antigen. 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

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WHEN TO REFER

PSA: prostate specific antigen. 1. Expert opinion of planning committee. December 1, 2012.

When should a patient be referred to a urologist? Q

• Prostatic abnormality

• If PSA becomes persistently abnormal

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NON-RESPONSE TO TREATMENT


Why might a patient not respond to testosterone therapy? Q

• Non-compliance • Malabsorption (orally or through skin) • Insufficient dose • Unsatisfactory formulation • Symptoms unrelated to testosterone

deficiency other diagnosis?

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TAKE HOME MESSAGES

• Follow-up should occur every 3-6 months: • Monitor response to treatment

• Detect potential complications

• Assess need for dose adjustments

• Assess change in blood parameters

• Monitor for adverse events

• PSA/DRE testing

• If patients do not respond to therapy, consider issues related to compliance, dosing and administration before considering another diagnosis

DRE: digital rectal exam; PSA: prostate specific antigen.

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If left untreated, what are the consequences of testosterone

deficiency? 4

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LEARNING OBJECTIVES


• Recognize the consequences resulting from untreated testosterone deficiency

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Low testosterone levels have been associated with: • Sexual side effects • Metabolic syndrome • Psychological effects • Osteoporosis • Decreased muscle mass • Lower quality of life • Increased mortality rate • Increased cardiovascular risk

IF LEFT UNTREATED, WHAT ARE THE CONSEQUENCES OF TESTOSTERONE DEFICIENCY?

T: testosterone. 1. Maggi et al. J Sex Med. 2007;4:1056-69; 2. Shelton et al. Urol Clin North Am. 2012;39:63-75.

Click for data on the impact of low T in

these areas

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QUALITY OF LIFE

1. Novak et al. Maturitas. 2002;43:231-7.

Testosterone deficiency negatively impacts quality of life

Social functioning

Energy

Physical functioning

Socio-emotional

functioning Sexual

functioning

Mental functioning

Emotional functioning

Adapted from Novak et al.

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Men with a normal testosterone level (n=452)

Men with an equivocal testosterone level (n=240)

Men with a low testosterone level (n=166)

LOW T AND MORTALITY

Low endogenous testosterone levels are

associated with an increased risk in

mortality

T: testosterone. 1. Shores et al. Arch Intern Med. 2006;166:1660-5.

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LOW T AND CARDIOVASCULAR RISK

T: testosterone. 1. Keating et al. J Clin Oncol. 2006;24:4448-56; 2. Tsai et al. J Natl Cancer Inst. 2007;99:1516-24; 3. Ruige et al. Heart. 2011;97:870-5.

Key Finding

Keating et al. 20061

(Observational study)

Tsai et al. 20072 (Observational study)

Ruige et al. 20113

(Meta-analysis)

• 16% increase in the risk of coronary heart disease events (death or myocardial infarction) in patients on androgen deprivation therapy

• 2-fold increased risk of fatal cardiovascular events over 10-year period in men on androgen deprivation therapy

• In elderly men, low testosterone predicted increased risk for cardiovascular disease and/or mortality*

*It is unclear whether low testosterone has a direct negative effect, or whether it should be regarded as a ‘marker of poor health’.

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TAKE HOME MESSAGES

• Low testosterone levels are associated with: • Impaired sexual function

• Increased risk of metabolic syndrome

• Depressed mood

• Decreased bone mineral density and increased risk of fractures

• Reduced muscle mass

• Decreased quality of life

• Increased risk of all-cause and CVD mortality

• Increased CV risk

CVD: cardiovascular disease; CV: cardiovascular.

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What are the risks associated with testosterone therapy? 5

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LEARNING OBJECTIVES


• Identify the risks associated with testosterone therapy

• Evaluate the evidence surrounding testosterone therapy and prostate cancer, and assess the clinical impact for prostate cancer survivors

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WHAT ARE THE RISKS ASSOCIATED WITH TESTOSTERONE THERAPY?

*Result of supraphysiological levels of testosterone. BPH: benign prostatic hyperplasia; HDL: high density lipoprotein. 1. Bassil et al. Ther Clin Risk Manag. 2009;5:427-48; 2. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70.

• Stimulate growth of known prostate cancer • Worsen symptoms of significant BPH • Gynecomastia* • Erythrocytosis* • Testicular atrophy and infertility • Skin diseases • Sleep apnea • Lowering of HDL*

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TESTOSTERONE THERAPY AND PROSTATE CANCER

• Testosterone therapy is contraindicated in men with prostate cancer 1,2

• Fear of accelerating tumour growth

• Huggins and Hodges (1941): castration caused a decline in serum marker acid phosphatase3

• Testosterone caused an enhanced rate of growth of prostate cancer

• Fowler et al. (1981): testosterone administration resulted in an unfavourable response in 45 of 52 men with metastatic prostate cancer4

1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 3. Huggins et al. Cancer Res. 1941;1:293-7; 4. Fowler et al. J Urol. 1981;126:372-5.

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EMERGING VIEW OF TESTOSTERONE LEVELS AND PROSTATE CANCER

• Prostate cancer is largely unaffected by variations in serum testosterone levels within the naturally occurring ranges1

• TESTOSTERONE DEFICIENCY may be associated with:1,2

• Greater risk of prostate cancer

• High Gleason scores

• Worse stage at presentation

• Worse survival

• No recurrence of prostate cancer upon testosterone therapy3,4

1. Morgentaler. Urol Clin N Am. 2011;38:119-24; 2. Morgentaler.Eur Urol. 2006;50:935-9; 3. Kaufman et al. J Urol. 2004;172:920-2; 4. Khera et al. J Sex Med. 2009;6:1165-70.

Click for data

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REVISITING THE ORIGINAL EVIDENCE

• Increase in serum testosterone after androgen deprivation results in an increase in PSA, even in men without cancer1

• Huggins and Hodges: only 1 patient without prior androgen deprivation1,2

• Fowler et al: 4/52 men did not have prior androgen deprivation3

• 1 patient had an unfavourable result

• 3 patients continued to receive testosterone with no apparent negative effect

PSA: prostate specific antigen. 1. Morgentaler et al. Urol Clin N Am. 2011;38:119-24; 2. Huggins et al. Cancer Res. 1941;1:293-7; 3. Fowler et al. J Urol. 1981;126:372-5.

Suggests that the effect of testosterone on prostate cancer may be more benign than originally thought

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*Individualized approach for patients disease free for <2 years, with severe symptoms (i.e. suicidal). PSA: prostate specific antigen. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Bebb et al. BCMJ. 2011; 53:474-79.

TESTOSTERONE THERAPY IN PROSTATE CANCER SURVIVORS

How should a patient who has been successfully treated for prostate cancer be

managed for testosterone deficiency? Q • Testosterone therapy may be considered on an

individualized basis, in patients who have undergone radial prostatectomy and:1,2

• Have been disease free for >2 years*

• Have undetectable PSA levels

• No general recommendation due to lack of randomized-controlled trials1

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TESTOSTERONE THERAPY IN PATIENTS WITH BPH-LUTS

• Testosterone is contraindicated in men with severe BPH-LUTS (IPSS >19)1

• Original consensus: testosterone therapy may worsen symptoms of BPH1,2

• Current view: testosterone therapy improves LUTS in men with low testosterone and mild BPH3

• No compelling data to suggest that testosterone therapy contributes to worsening of LUTS or promotion of urinary retention3

BPH: benign prostatic hyperplasia; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Bassil et al. Ther Clin Risk Manag. 2009;5:427-48; 3. Shigehara et al. Aging Male. 2011 Mar;14:53-8.

Click for data

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TAKE HOME MESSAGES

• Risks are associated with testosterone therapy and should be discussed and monitored in patients

• Prostate cancer is largely unaffected by variations in serum testosterone levels within the naturally occurring ranges

• Testosterone therapy may be considered on an individualized basis, in patients who have undergone radial prostatectomy and • Have been prostate cancer free for >2 years

• Have undetectable PSA levels

PSA: prostate specific antigen.

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LOW TESTOSTERONE

Does testosterone therapy impact comorbid conditions? 6

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LEARNING OBJECTIVES


• Recognize the benefits of testosterone therapy on sexual function, including the role of testosterone therapy in PDE5 inhibitor non-responders

• Assess the impact of testosterone therapy on cardiovascular events

• Evaluate the benefits of testosterone therapy in patients with HIV and the implications on clinical practice

• Assess the role of testosterone therapy in improving quality of life and pain in chronic opioid users

PDE5: phosphodiesterase type 5.

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DOES TESTOSTERONE THERAPY IMPACT COMORBID CONDITIONS?

Testosterone therapy can impact: • Sexual function • Cardiovascular disease • HIV • Chronic narcotic use

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IMPACT ON SEXUAL FUNCTION

1. Isidori et al. Clin Endocrinol (Oxf). 2005;63:381-94.

Testosterone therapy can result in moderate improvements to all

aspects of sexual function1

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TESTOSTERONE AND SEXUAL DYSFUNCTION

• Testosterone therapy has been evaluated in context of: • Erectile function

• Libido

• Ejaculatory function

• Overall sexual satisfaction

• Testosterone therapy results in moderate improvements to all aspects of sexual function

1. Isidori et al. Clin Endocrinol (Oxf). 2005;63:381-94.

Click for data

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IMPLICATIONS FOR CLINICAL PRACTICE

• Testosterone therapy benefits men with underlying sexual dysfunction

• Clinicians should consider testosterone therapy for:1

• Men with low testosterone and libido

• Men with ED and low testosterone, after evaluating cause of ED and considering established therapies


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ROLE OF TESTOSTERONE IN ERECTILE FUNCTION

cGMP: cyclic guanosine monophosphate; GMP: guanosine monophosphate; NO: nitric oxide; NOS: nitric oxide synthase; PDE5: phosphodiesterase type 5; PDE5i: phosphodiesterase 5 inhibitor; T: testosterone. 1.Park et al. BJU Int. 2005;95:366-70; 2. Buvat et al. Current Sexual Health Reports. 2008;5:135-40.

• Testosterone modulates NOS and PDE5 expression

• Low serum testosterone levels are a predictor of poor response to PDE5i1

• Combined use of testosterone and PDE5i salvaged 37.5-92% of PDE5i failures2

Smooth muscle

contraction Smooth muscle relaxation

cGMP

cGMP

GMP

PDE5i

Click for data

T cGMP NOS NO

PDE5i

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TESTOSTERONE AND PDE5i: IMPLICATIONS FOR CLINICAL PRACTICE

PDE5i: phosphodiesterase 5 inhibitor. 1. Buvat et al. J Sex Med. 2010;7:1627-56; 2. Buvat et al. Current Sexual Health Reports. 2008;5:135-40.

• Measure testosterone levels in PDE5i non-responders1

• Consider combination therapy when:1,2

• Testosterone deficiency is diagnosed following a consultation for ED

• Poor response to PDE5i therapy alone due to unsatisfying erections in patients with low or low-normal testosterone

• Poor response to PDE5i therapy alone due to sexual desire in patients with low or low-normal testosterone

• No improvement on testosterone therapy alone in testosterone deficient men1

How do these findings relate to clinical practice? Q

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IMPACT ON CARDIOVASCULAR DISEASE

Testosterone therapy does not increase cardiovascular risk and has been reported to

have beneficial effects on patients with angina and heart failure1-3

1. Toma et al. Circ Heart Fail. 2012;5:315-21; 2. Malkin et al. Heart. 2004;90:871-6; 3. Carson et al. J Sex Med. 2012;9:54-67.

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CARDIOVASCULAR EVENTS NOT AFFECTED BY TESTOSTERONE TREATMENT

*Odds ratio significantly different from placebo. CABG: coronary artery bypass graft. 1. Calof et al. J Gerontol A Biol Sci Med Sci. 2005;60:1451-7; 2. Carson et al. J Sex Med. 2012;9:54-67.

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TOM TRIAL

• Investigated testosterone administration on lower extremity strength and physical function

• 209 men enrolled in the study: • Were ≥65 years of age

• Had total serum testosterone levels between 3.5 to 12.1 nmol/L

• Had limitations in mobility

1. Basaria et al. NEJM. 2010;363:109-22.

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TOM TRIAL: TESTOSTERONE INCREASED CV RISK

Trial halted due to an increased risk of CV adverse events in the testosterone arm1

MedDRA: Medical Dictionary for Regulatory Activities. 1. Basaria et al. NEJM. 2010;363:109-22.

Risk of adverse events with testosterone therapy

Total Risk Odds Ratio (95% CI)

Event Category Unadjusted Adjusted

MedDRA cardiac 10.6 (1.3-84.5) NA

Atherosclerosis-related 7.2 (0.9-59.7) NA

Cardiovascular-related 5.4 (2.0-14.9) 5.8 (2.0-16.8)

Dermatologic 2.6 (1.1-6.2) 4.9 (1.7-14.6)

Necessitating referral for medical evaluation

2.3 (0.98-5.3) 5.2 (1.8-14.6)

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TOM TRIAL: LIMITATIONS

• Study limitations:1,2,3

• Small sample size

• Older, sicker (unique) population

• Study not designed to assess CVD

• More patients in the testosterone arm had hypertension or dyslipidemia, increasing their risk of CVD

CVD: cardiovascular disease. 1. Basaria et al. NEJM. 2010;363:109-22; 2. Traish et al. Am J Med. 2011;124:578-87; 3. Bebb. BCMJ. 2011; 53:474-79.

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BENEFITS OF TESTOSTERONE THERAPY IN PATIENTS WITH CVD

• Testosterone therapy improves exercise capacity in patients with heart failure1

• Improvements are greater than that observed with other therapies currently used for morbidity and mortality reduction in patients with heart failure

• Testosterone therapy in hypogonadal men with angina significantly improved time to ischemic threshold vs. placebo2

CVD: cardiovascular disease. 1. Toma et al. Circ Heart Fail. 2012;5:315-21; 2. Malkin et al. Heart. 2004;90:871-6.

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TESTOSTERONE THERAPY AND HIV

1. Rietschel et al. Clin Infect Dis. 2000;31:1240-4; 2. Rabkin et al. Arch Gen Psychiatry. 2000;57:141-7.

• 20-25% of HIV-infected men on highly active antiretroviral therapy have low testosterone levels1

• In men with low testosterone and HIV, testosterone therapy has been shown to:2

• Restore libido and energy • Alleviate depressed mood • Increase muscle mass

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IMPACT OF TESTOSTERONE THERAPY ON PATIENTS WITH HIV

1.Rabkin et al. Arch Gen Psychiatry. 2000;57:141-7.

0 20 40 60 80

Libido

ED

Energy

Mood

Patients Reporting Improvements (%)

Placebo

Testosterone

• Average increase in muscle mass over 12 weeks was 1.6 kg • A 2.2 kg increase was reported for the subset with wasting at baseline

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IMPLICATIONS FOR CLINICAL PRACTICE

• Short-term testosterone therapy should be considered as an adjunct to antiretroviral therapy in HIV-infected men with low testosterone levels and weight loss, to promote:

• Weight maintenance

• Gains in lean body mass and muscle strength

• Measure bioavailable testosterone in men with HIV infection • These men have elevated SHBG

SHBG: sex hormone binding globulin. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

Click for factors that influence SHBG

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IMPACT ON CHRONIC OPIOID USE

1. Daniell et al. J Pain. 2006;7:200-10; 2. Aloisi et al. Reprod Biol Endocrinol. 2011;9:26.

Testosterone therapy improves quality of life and pain indices in patients on chronic opioids

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IMPACT OF CHRONIC OPIOID USE ON TESTOSTERONE LEVELS

DHEAS: dehydroepiandrosterone sulfate; FSH: follicle stimulating hormone; GnRH: gonadatropin releasing hormone; LH: luteinizing hormone. 1. Katz et al. Clin J Pain. 2009;25:170-5; 2. Roberts et al. Clin J Pain. 2002;18:144-8.

• Chronic opioid use leads to a down-regulation of testosterone production through:1,2

• Secondary hypogonadism

• Decreased hypothalamic GnRH

• Decreased pituitary LH, possibly FSH

• Decreased adrenal DHEAS and testosterone

• Decreased testicular testosterone

• Possible cortisol deficiency

• Possible growth hormone deficiency

• Bioavailable testosterone should be measured in chronic opioid users

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TESTOSTERONE THERAPY IMPROVES SYMPTOMS IN PATIENTS ON OPIOIDS

• Testosterone therapy has been shown to improve patient quality of life, with improvements in:1

• Sexual function

• Mood

• Depression

• Hematocrit levels

• Testosterone therapy improves pain dimensions2

1. Daniell et al. J Pain. 2006;7:200-10; 2. Aloisi et al. Reprod Biol Endocrinol. 2011;9:26.

Click for data on the impact of testosterone therapy in opioid users

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TAKE HOME MESSAGES

• Testosterone therapy has been shown to: • Improve sexual function

• Improve PDE5 inhibitor efficacy*

• Have no significant impact on CV event rates

• Improve libido, energy, mood and muscle mass in men with HIV

• Improve quality of life and pain indexes in chronic opioid users

*In patients with low-normal serum testosterone levels who have previously failed on PDE5 inhibitor therapy alone. CV: cardiovascular; PDE5: phosphodiesterase type 5.

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7

Supplementary Slides

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ADAM QUESTIONNAIRE

• Correlates symptoms with serum testosterone levels with 88% sensitivity and 60% specificity

Return to Slide 9

ADAM: androgen deficiency in aging males. 1. Morley et al. Metabolism. 2000;49:1239-42.

ADAM Questionnaire1

1. Do you have a decrease in libido (sex drive)?

2. Do you have a lack of energy?

3. Do you have a decrease in strength and/or endurance?

4. Have you lost height?

5. Have you noticed a decreased ‘‘enjoyment of life’’?

6. Are you sad and/or grumpy?

7. Are your erections less strong?

8. Have you noted a recent deterioration in your ability to play sports?

9. Are you falling asleep after dinner?

10. Has there been a recent deterioration in your work performance?

A positive questionnaire result is defined as a

‘‘yes’’ answer to Questions 1 or 7 or any

3 other questions

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FREE AND BIOAVAILABLE TESTOSTERONE CALCULATOR

Return to Slide 15

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THE INFLUENCE OF SHBG

• SHBG-bound testosterone represents the majority of testosterone it is not biologically active

[SHBG]: concentration of sex hormone binding globulin. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 3. Morales et al. CUAJ. 2010;4:269-75.

Factors that Influence [SHBG]1

Decrease in [SHBG] Increase in [SHBG]

Obesity Aging

Diabetes Hepatic cirrhosis

Hypothyroidism Hyperthyroidism

Nephrotic syndrome HIV infection

Use of glucocorticoids, progestins and androgenic steroids

Estrogens

Return to Slide 15

• Influences interpretation of total testosterone measurement

• Use free or bioavailable measurements when altered SHBG

is suspected2,3

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Abnormal PSA/DRE

TREATING PRIMARY/SECONDARY HYPOGONADISM

DRE: digital rectal exam; FSH: follicle-stimulating hormone; LH: luteinizing hormone; MRI: magnetic resonance imaging; PSA: prostate specific antigen; T: testosterone; TRT: testosterone replacement therapy. 1. Morales et al. CUAJ. 2010;4:269-75.

Return to Slide 19

Primary Hypogonadism (testicular)

Low T + High LH/FSH

Secondary Hypogonadism (pituitary/hypothalamic) Low T + Normal LH/FSH

Investigate or Refer

Consider TRT

Monitor

Continue TRT Consider: •Compliance •Dose adjustments •Change in delivery system •Other causes •Referral

Treat or Refer Investigate

or Refer

Define Etiology

Order MRI or Refer

Response No Response

Normal PSA/DRE

Abnormal PSA/DRE

Normal PSA/DRE

High Prolactin Normal Prolactin

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FORMULATIONS UNDER INVESTIGATION

• Novel testosterone formulations are being developed with better pharmacokinetic and more selective activity profiles:

• Biodegradable testosterone microspheres

• Long-acting testosterone esters

• Buccal and auxiliary formulations

• Nasal sprays

1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70.

Next

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OTHER TESTOSTERONE FORMULATIONS

These products are currently not available in Canada. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.

Testosterone pellets

Injectable long-acting testosterone undecanoate in oil

Buccal bio-adhesive testosterone tablets

Testosterone in-adhesive matrix patch

Next

High concentration testosterone gels

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NOVEL COMPOUNDS FOR ANDROGEN THERAPY

• 7-alpha-methyl-19-nortestosterone: • Greater agonist activity on muscle and gonadotrophin suppression

• Less activity on the prostate

• Selective androgen receptor modulators (SARMs): • May selectively exert androgen activity on muscle, bone and sexual function

• Minimal action on prostate and cardiovascular system

1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70.

Return to Slide 26

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IMPACT OF LOW T

MetS: metabolic syndrome; T: testosterone. 1. Corona et al. Int J Impot Res. 2004;16:275-81; 2. Corona et al. J Sex Med. 2008;5:1991-8; 3. Kupelian et al. J Clin Endocrin Metab. 2006;91:843-50; 4. Barrett-Connor et al. J Clin Endocrinol Metab. 1999;84:573.

Key Finding

Sexual Dysfunction Corona et al. 20041 Corona et al. 20082

• Patients with ED and hypoactive sexual desire had a

significantly lower T level • Men with delayed ejaculation had the highest prevalence of

testosterone deficiency

Metabolic Syndrome Kupelian et al. 20063

• Non-obese men with a low baseline T level had a

2- to 4-fold increased risk of developing MetS

Psychological effects Barrett-Connor et al. 19994

• Bioavailable T levels were 17% lower for men with

depression than levels observed in all other men

Next

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IMPACT OF LOW T

T: testosterone. 1. Jackson et al. Am J Med Sci. 1992;304:4-8; 2. Meier et al. Arch Intern Med. 2008;168:47; 3. Szulc et al. Am J Clin Nutr. 2004;80:496.

Return to Slide 61

Key Finding

Osteoporosis Jackson et al. 19921

Meier et al. 20082

• Testosterone deficiency was found in 71% men with hip

fracture vs. 32% of the controls • Lower testosterone was associated with ↑ risk of fracture

Muscle Mass Szulc et al. 20043

• Men with low testosterone levels had a significantly lower

relative appendicular skeletal muscle mass index than men with higher testosterone levels

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TESTOSTERONE THERAPY IN PROSTATE CANCER SURVIVORS

PSA: prostate specific antigen. 1. Kaufman et al. J Urol. 2004;172:920-2; 2. Agarwal et al. J Urol. 2005;173:533-6; 3. Sarosdy MF. Cancer. 2007;109:536-41; 4. Khera et al. J Sex Med. 2009;6:1165-70; 5. Morgentaler. J Sex Med. 2009;6:574-7.

Key Finding

Kaufman et al. 20041 • 7 men: radial prostatectomy, undetectable PSA • No recurrences of prostate cancer detected over 1-12 years of therapy

Agarwal et al. 20052 • 10 men: radial prostatectomy, undetectable PSA • No recurrence of prostate cancer over 19-month follow-up

Sarosdy et al. 20073 • 31 men: brachytherapy for prostate cancer treatment • Median duration of treatment 4.5 years • No recurrence or prostate cancer progression

Khera et al. 20094 • 57 men: radial prostatectomy, undetectable PSA • Testosterone therapy for average 36 months followed for average

13 months • No recurrence of prostate cancer or increase in PSA values

Morgentaler et al. 20095 • 84 year old man, untreated prostate cancer • Received 2 years of testosterone therapy • No increase in PSA levels Return to

Slide 70

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TESTOSTERONE THERAPY IMPROVES LUTS IN PATIENTS WITH LOW T AND MILD BPH-LUTS

T: testosterone; ART: androgen replacement therapy; IPSS: International Prostate Symptom Score. 1. Shigehara et al. Aging Male. 2011;14:53-8.

Return to Slide 73

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TESTOSTERONE THERAPY IMPROVES SEXUAL FUNCTION

T: testosterone. 1. Isidori et al. Clin Endocrinol (Oxf). 2005;63:381-94.

Testosterone therapy results in:

Significant, moderate improvement of all aspects of

sexual function in men with low or low-normal testosterone

levels1

Return to Slide 79 -2 -1 0 1 2 3 4 5 6

All sexual domains (SMD)

Studies with baseline T <10 nmol/L

Sexual Motivation

Erectile Function

Morning Erections

Intercourse

Sexual Satisfaction

Sexual Thoughts

Total Erections

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TESTOSTERONE THERAPY AND PDE5i EFFICACY

IIEF-5: international index of erectile function; PDE5i: phosphodiesterase 5 inhibitor; T: testosterone. 1. Rosenthal et al. 2006;67:571-4; 2. Buvat et al. J Sex Med. 2011;8:284-93; 3. Shamloul et al. J Sex Med. 2005;2:559-64; 4. Hwang et al. Int J Impot Res. 2006;18:400-4; 5. Shabsigh et al. J Urol. 2004;172:658-63; 6. Buvat et al. Current Sexual Health Reports. 2008;5:135-40.

Overall combined use of testosterone and PDE5 inhibitors salvaged 37.5-92% of PDE5i failures6

Study Therapy Key Finding

Rosenthal 20061

• Testosterone gel + sildenafil

• After 16 weeks, 92% of men had improved potency and erection quality with combination therapy

Buvat 20112

• Testosterone gel + tadalafil

• Significant improvement of erectile function with addition of testosterone therapy compared to placebo when T ≤300 ng/dL

Shamloul 20053

• Testosterone undecanoate + sildenafil

• Patients receiving combination therapy showed significant improvement in IIEF-5 scores

Hwang 20064

• Testosterone undecanoate ± sildenafil

• One third of non-responders responded to testosterone therapy alone

• Another third of non-responders showed response to sildenafil after normalization of testosterone

Shabsigh 20055

• Testosterone gel + sildenafil

• Testosterone-treated subjects had greater improvement in erectile function compared to those who received placebo.

Return to Slide 81

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THE INFLUENCE OF SHBG

• SHBG-bound testosterone represents the majority of testosterone it is not biologically active

[SHBG]: concentration of sex hormone binding globulin; T: testosterone. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 3. Morales et al. CUAJ. 2010;4:269-75.

Factors that Influence [SHBG]1

Decrease in [SHBG] Increase in [SHBG]

Obesity Aging

Diabetes Hepatic cirrhosis

Hypothyroidism Hyperthyroidism

Nephrotic syndrome HIV infection

Use of glucocorticoids, progestins and androgenic steroids

Estrogens

Return to Slide 91

• Influences interpretation of total testosterone measurement

• Use free or bioavailable measurements when altered SHBG

is suspected2,3

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TESTOSTERONE THERAPY IMPROVES SYMPTOMS IN PATIENTS ON OPIOIDS

ADSQ: androgen deficiency symptoms questionnaire. *p<0.001; †p<0.01; ‡p<0.05 1. Daniell et al. J Pain. 2006;7:200-10.

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Decreased libido

ED Tiredness Depressed mood

Hot flashes/ night sweats

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TESTOSTERONE THERAPY IMPROVES PAIN DIMENSIONS

QUID: an Italian pain questionnaire which measures the quality and intensity of the current pain experience. 1. Aloisi et al. Reprod Biol Endocrinol. 2011;9:26.

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Sensory Afffective Evaluative Miscellaneous Total

QU

ID V

alu

e

QUID parameters

Baseline

12 Monthsp<0.02

p<0.02

p<0.01

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