Update on Hypogonadism and - Grant/Downing€¦ · Update on Hypogonadism and Testosterone...

Update on Hypogonadism and Testosterone Replacement Therapy

The Primary Care Perspective

Update on Hypogonadism and Testosterone Replacement Therapy

The Primary Care Perspective

Martin Miner MD

Clinical Associate Professor of Family Medicine

Warren Alpert School of Medicine

Brown University

Co-Director Men’s Health Center

Miriam Hospital

Providence, RI

Martin Miner MD

Clinical Associate Professor of Family Medicine

Warren Alpert School of Medicine

Brown University

Co-Director Men’s Health Center

Miriam Hospital

Providence, RI

3

DisclosuresDisclosures

Dr Miner: consultant: Auxilium Pharmaceuticals, Inc., Bayer Schering Pharma, BoehringerIngelheim, Endo Pharmaceuticals

Research support: GSK

Dr Miner: consultant: Auxilium Pharmaceuticals, Inc., Bayer Schering Pharma, BoehringerIngelheim, Endo Pharmaceuticals

Research support: GSK

4

Learning ObjectivesLearning Objectives

Explain the role of testosterone in overall health and the burden of testosterone deficiency

Recognize the role of hypogonadism in obesity, metabolic syndrome, diabetes, cardiovascular disease, and erectile dysfunction (ED)

Identify the signs and symptoms of hypogonadism and their complex clinical presentation

List the options available to treat hypogonadism

Monitor potential adverse effects of treatment

Explain the role of testosterone in overall health and the burden of testosterone deficiency

Recognize the role of hypogonadism in obesity, metabolic syndrome, diabetes, cardiovascular disease, and erectile dysfunction (ED)

Identify the signs and symptoms of hypogonadism and their complex clinical presentation

List the options available to treat hypogonadism

Monitor potential adverse effects of treatment

5

How Is HypogonadismDefined?

How Is HypogonadismDefined?

● “Hypogonadism is a clinical condition characterized by low serum testosterone levels occurring in association specific signs and symptoms.”

●Other terminologies for hypogonadism

Decline of testosterone and male androgens in men of any age

Andropause: hypogonadism in older men or androgen deficiency in aging men (ADAM)

Late-onset hypogonadism (LOH)

Partial androgen deficiency in aging men (PADAM)

● “Hypogonadism is a clinical condition characterized by low serum testosterone levels occurring in association specific signs and symptoms.”

●Other terminologies for hypogonadism

Decline of testosterone and male androgens in men of any age

Andropause: hypogonadism in older men or androgen deficiency in aging men (ADAM)

Late-onset hypogonadism (LOH)

Partial androgen deficiency in aging men (PADAM)Rhoden EL, Morgentaler A. N Engl J Med. 2004;350:482-492.

6

How Is HypogonadismDefined?

How Is HypogonadismDefined?

A symptom complex in the presence of low levels of testosterone1,2

Age-related changes in physiologic function affected by testosterone levels2

Increased BMILow bone mineral densityReduced cognition and memory Depressed moodDecreased sexual desire and functionReduced strength and energy

A symptom complex in the presence of low levels of testosterone1,2

Age-related changes in physiologic function affected by testosterone levels2

Increased BMILow bone mineral densityReduced cognition and memory Depressed moodDecreased sexual desire and functionReduced strength and energy

BMI = body mass index.1. Morley JE et al. Metabolism. 2000;49:1239-1242. 2. Bhasin S et al. J Clin Endocrinol Metab.

2006;91:1995-2010.

71. AACE Hypogonadism Task Force. Endocr Pract. 2002;8:439-456. 2. Bhasin S et al. J Clin Endocrinol Metab.

2006;91:1995-2010. 3. Mulligan T et al. Int J Clin Pract. 2006;60:762-769.

Clinical Manifestations of Hypogonadism

Clinical Manifestations of Hypogonadism

Physical/Metabolic Psychological1,2 Sexual1,2

• Decreased bonemineral density1,2

• Decreased musclemass and strength1,2

• Gynecomastia1,2

• Anemia1,2

• Frailty3

• Increased body fat or BMI1,2

• Fatigue1,2

• Insulin resistance

• Depressed mood• Diminished energy,

sense of vitality, orwell-being

• Impaired cognitionand memory

• Diminished libido• Erectile dysfunction• Difficulty

achieving orgasm• Decreased spontaneous

erections

Production and Regulation of TestosteroneProduction and Regulation of Testosterone

HypothalamusGnRH

Pituitary

Testes

FSHandLH

(Leydig cells) (Sertoli cells)

Testosterone Spermatogenesis

Testes++

+ -

- -

+- S. Urquhart 2007

9

Classification of Hypogonadism

Classification of Hypogonadism

Primary1,2 Secondary1,2 Mixed2

Dual HPGAxis Defects

• Hemochromatosis

• Sickle cell disease

• Thalassemia

• Glucocorticoidtreatment

• Alcoholism

PituitaryCauses

• Hypopituitarism

• Pituitary tumors:

• Ischemia

• Space Occupying Lesions

• Granulomatousdisease

HypothalamicCauses

• Kallmann syndrome

• Constitutional delay in growth and development

• Chronic illnesses

TesticularDisorders

• Klinefelter syndrome

• Orchitis

• Congenital or acquired anorchia

• Testicular tumors

• Testicular Torsion

HPG = hypothalamic-pituitary-gonadal.1. AACE Hypogonadism Task Force. Endocr Pract. 2002;8:439-456. 2. Bhasin S et al. J Clin Endocrinol Metab.

2006;91:1995-2010.

Epidemiology and Prevalence of Hypogonadism: The Baltimore Aging Study

Epidemiology and Prevalence of Hypogonadism: The Baltimore Aging Study

Harman SM, et al. J Clin Endocrinol Metab. 2001;86:724-731.

Perc

enta

ge

60 - 69

12%12%19%19%

28%28%

49%49%

50 - 59 70 - 79 80+

Age in Years

Percentage of men, by decade, with a testosterone valuein the hypogonadal range—total T <11.3 nmol/L (325 ng/dL)

Prevalence of Symptomatic Androgen Deficiency in Men

Prevalence of Symptomatic Androgen Deficiency in Men

Boston Area Community Health

N=1,475 men, aged 39-79 (better ethnic mix)

24% of the men had TT <300 ng/dL

11% of the men had free T <5 ng/mL

Crude prevalence of symptomatic hypogonadismwas 5.6%

Increases substantially with age

Better overall estimate is that 4-5 million men in the US have hypogonadism

Boston Area Community Health

N=1,475 men, aged 39-79 (better ethnic mix)

24% of the men had TT <300 ng/dL

11% of the men had free T <5 ng/mL

Crude prevalence of symptomatic hypogonadismwas 5.6%

Increases substantially with age

Better overall estimate is that 4-5 million men in the US have hypogonadism

Araujo et al (NERI) J Clin Endo Metab 2007; 92: 4241-4247

12

Prevalence and Under-treatmentin the United States

Prevalence and Under-treatmentin the United States

BACH, Boston Area Community Health Survey.1. Araujo AB et al. J Clin Endocrinol Metab. 2007;92:4241-4247. 2. Reproduced with permission from Hall SA et al.

Arch Intern Med. 2008;168:1070-1076. 3. IMS Health analyzes testosterone use in U.S. IMS Health Web site. http://www.imshealth.com/portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f611019418c22a/?vgnextoid=

77d68ede1ca19110VgnVCM10000071812ca2RCRD&vgnextfmt=default. Accessed September 18, 2009.

819,000 men receive testosterone therapy3

(breakdown by age)BACH Survey estimated crude

prevalence of symptomatic androgen deficiency is 5.6%1

2

Wei

ghte

d P

reva

lenc

e (%

)

Treated12.2%

Symptomaticuntreated

87.8%

1%>65 y

46-65 y

18-45 y

<18 y

Hypogonadism in MalesHIM Study

Hypogonadism in MalesHIM Study

An Epidemiological Study to Estimate the Population Prevalence of Hypogonadism

in the US

Mulligan T, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM Study. Int J Clin Pract 2006; 60:762-9

An Epidemiological Study to Estimate the Population Prevalence of Hypogonadism

in the US

Mulligan T, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM Study. Int J Clin Pract 2006; 60:762-9

Hypogonadism in MalesHIM Study

An Epidemiological Study to Estimate the Population Prevalence of Hypogonadism in the US

Hypogonadism in MalesHIM Study

An Epidemiological Study to Estimate the Population Prevalence of Hypogonadism in the US

2650 sites contacted

95 sites enrolled patients in 25 states47 Family Practice, 44 Internal Medicine, 3 Endocrinology, 1 Urology

2,165 patients enrolled

Prevalence of hypogonadism: 38.7%Hypogonadism: TT < 10.4 nmol/L

2650 sites contacted

95 sites enrolled patients in 25 states47 Family Practice, 44 Internal Medicine, 3 Endocrinology, 1 Urology

2,165 patients enrolled

Prevalence of hypogonadism: 38.7%Hypogonadism: TT < 10.4 nmol/L

Mulligan, Mulligan, IntInt J J ClinClin PractPract 2006; 60: 7622006; 60: 762--99

The Prevalence of Low Testosterone Increases with Age (<300 ng/dL)

The Prevalence of Low Testosterone Increases with Age (<300 ng/dL)

45 to 54 55 to 64 65 to 74 75 to 84 85+ Total0

10

20

30

40

50

60

70

38.7(36.6–40.7)

50.0(32.7–67.3)

45.5 (39.0–52.1)39.9

(35.4–44.4)40.2

36.6–43.8)34.0

(30.6–37.4)

Patient Age Range

Pre

vale

nce

of L

ow T

in A

ll E

nrol

led

Pat

ient

s (%

, 95%

CI)

Mulligan, et al. Int J Clin Pract. 2006 Jul;60(7):762–769.

Over 1/3 of men over 45 years of age have a low testosterone level

Co-Morbidities in Hypogonadal MenMulligan, Int J Clin Pract 2006; 60: 762-9

Co-Morbidities in Hypogonadal MenMulligan, Int J Clin Pract 2006; 60: 762-9

* P = <0.001

Odds Ratio of Selected Co-Existing Diseases

Mulligan, Int J Clin Pract 2006; 60: 762-9

Odds Ratio of Selected Co-Existing Diseases

Mulligan, Int J Clin Pract 2006; 60: 762-9

Medical ConditionsMedical Conditions Odds Ratio (95% C.I.)Odds Ratio (95% C.I.)

ObesityObesity 2.33 (1.90, 2.85)2.33 (1.90, 2.85)

DiabetesDiabetes 2.04 (1.67, 2.50)2.04 (1.67, 2.50)

HypertensionHypertension 1.80 (1.50, 2.14)1.80 (1.50, 2.14)

OsteoporosisOsteoporosis 1.59 (0.77, 3.30)1.59 (0.77, 3.30)

Rheumatoid ArthritisRheumatoid Arthritis 1.55 (0.91, 2.62)1.55 (0.91, 2.62)

HyperlipidemiaHyperlipidemia 1.49 (1.25, 1.78)1.49 (1.25, 1.78)

Asthma/COPDAsthma/COPD 1.42 (1.07, 1.88)1.42 (1.07, 1.88)

Chronic PainChronic Pain 1.20 (0.95, 1.50)1.20 (0.95, 1.50)

Prostate DiseaseProstate Disease 1.19 (0.95, 1.49)1.19 (0.95, 1.49)

18

Case Study: AdamCase Study: AdamA 48-year-old man presents with ED, fatigue,

depressed mood, and distress in the marital relationship. Low libido. Medical history otherwise unremarkable

Weight 220 lb BMI 35.5

Height 5’ 6’’

Waist circumference 44”

BP 140/90

Genital exam normal

DRE normal

A 48-year-old man presents with ED, fatigue, depressed mood, and distress in the marital relationship. Low libido. Medical history otherwise unremarkable

Weight 220 lb BMI 35.5

Height 5’ 6’’

Waist circumference 44”

BP 140/90

Genital exam normal

DRE normalDRE = digital rectal exam.

19

What would be your next step?What would be your next step?

PDE5 = phosphodiesterase type 5.

1. Refer to marital counseling

2. Refer to psychiatrist

3. Order labs including testosterone

4. Prescribe PDE5 inhibitor and check testostoerone

5. Prescribe testosterone

1. Refer to marital counseling

2. Refer to psychiatrist

3. Order labs including testosterone

4. Prescribe PDE5 inhibitor and check testostoerone

5. Prescribe testosterone

20

Low Testosterone Also PredictsAll-Cause Mortality in Older MenLow Testosterone Also PredictsAll-Cause Mortality in Older Men

Laughlin G, et al. J Clin Endocrinol Metab. 2008;93:68-75.

PopulationPopulation--based Studybased Study——1212--Year FollowYear Follow--upup

Testosterone Testosterone ((ng/dLng/dL))

Median Hormone Median Hormone Level (Level (ng/dLng/dL))

Adjusted HR (95% CI)*Adjusted HR (95% CI)*

>370>370 436436 1.001.00

300300--370370 331331 0.93 (0.73, 1.19)0.93 (0.73, 1.19)

241241--299299 273273 1.15 (0.90, 1.47)1.15 (0.90, 1.47)

<241<241 204204 1.44 (1.12, 1.84)1.44 (1.12, 1.84)

PP for trend = 0.002for trend = 0.002

*Adjusted for age, BMI, waist-hip ratio, alcohol use, current smoking, exercise

Men with low and equivocal serum T levels had increased all-cause mortality and shorter survival times.

•VA Puget Sound study of 858 men•8 year follow-up

•Low T <250 ng/dLor a free T <0.75

ng/dL•All-cause mortality was 34.9% in men

with low T and 20.1% in men with normal T.

Low Testosterone Levels are Associated with an Increased Mortality Rate

Low Testosterone Levels are Associated with an Increased Mortality Rate

Shores MM. Arch Intern Med. 2006;166(15):1660-1665

EPICEPIC--Norfolk Study: Testosterone Levels are Norfolk Study: Testosterone Levels are Related to AllRelated to All--Cause and CVD MortalityCause and CVD Mortality

Increasing endogenous Testosterone levels are inversely related to mortality due to all causes, CV causes, and cancer.

N-2314 men aged 42-78 y.Khaw KT et al. Circulation 2007;116(23):2694-2701

23

In spite of differences among various labs, total testosterone level is commonly

considered hypogonadal when it is below:

In spite of differences among various labs, total testosterone level is commonly

considered hypogonadal when it is below:

1. 400 ng/dL

2. 300 ng/dL

3. 200 ng/dL

4. 100 ng/dL

5. 50 ng/dL

1. 400 ng/dL

2. 300 ng/dL

3. 200 ng/dL

4. 100 ng/dL

5. 50 ng/dL

International Society for the Study of the Aging Male (ISSAM) and European Academy of

Andrology (EAU) Guidelines 2008

International Society for the Study of the Aging Male (ISSAM) and European Academy of

Andrology (EAU) Guidelines 2008

●Total T: drawn between 7:00 am -11am

●No lower limit for normal

●Total T > 12 nmoL/l (350 ng/dL) do not generally require repletion

●Patients with Total T < 8 nmoL/l (230 ng/dL) will usually benefit from T Rx

●Total T: drawn between 7:00 am -11am

●No lower limit for normal

●Total T > 12 nmoL/l (350 ng/dL) do not generally require repletion

●Patients with Total T < 8 nmoL/l (230 ng/dL) will usually benefit from T Rx

24

Androgen Deficiency in Hypogonadal MenLaboratory Diagnosis

Androgen Deficiency in Hypogonadal MenLaboratory Diagnosis

If repeat serum total T between 250 and 350 ng/dL

Measure serum free T level by equilibrium dialysis

or Measure serum SHBG

and calculate free T or bioavailable T (bT)

If repeat serum total T between 250 and 350 ng/dL

Measure serum free T level by equilibrium dialysis

or Measure serum SHBG

and calculate free T or bioavailable T (bT)

SHBG

ALB

FreeEquilibrium

dialysis or

calc free TDirect

measurement of non-SHBG-

bound T or calculate

bioavailable T

26

What Level of Serum Testosterone Is Diagnostic for Hypogonadism?

What Level of Serum Testosterone Is Diagnostic for Hypogonadism?

●AACE GuidelinesTT* <200 ng/dL

Free T <50 pg/mL

Bioavailable T <70 ng/dL

●Endocrine Society GuidelinesTT <200 ng/dL = diagnostic

TT 200-320 ng/dL = equivocal range of hypogonadism

Free T <6.5 ng/dL or bioavailable T <15 ng/dL differentiates eugonadism from hypogonadism

● ISA, ISSAM, EAU: TT <346 ng/dL If TT < 150, order Proactin level

●AACE GuidelinesTT* <200 ng/dL

Free T <50 pg/mL

Bioavailable T <70 ng/dL

●Endocrine Society GuidelinesTT <200 ng/dL = diagnostic

TT 200-320 ng/dL = equivocal range of hypogonadism

Free T <6.5 ng/dL or bioavailable T <15 ng/dL differentiates eugonadism from hypogonadism

● ISA, ISSAM, EAU: TT <346 ng/dL If TT < 150, order Proactin level

*Most frequently used laboratory test for the diagnosis of hypogonadism.ISA = International Society of Andrology; ISSAM = International Society for the Study of the Aging Male; EAU = European Association of

Andrology

AACE Hypogonadism Task Force. Endocr Pract. 2002;8:440-456; Rosner W, et al. J Clin Endocrinol Metab. 2007; 92:405-413; Nieschlag E, et al. J Androl. 2006;27:135-137.

27

What Testosterone Level Warrants Treatment?

What Testosterone Level Warrants Treatment?

●Total testosterone <300 ng/dL

US Food and Drug Administration

American Society of Andrology

Endocrine Society 2006

●Total testosterone <300 ng/dL

US Food and Drug Administration

American Society of Andrology

Endocrine Society 2006

ASA Position Statement. J Androl. 2006; 27:133-134; Rosner W, et al. J ClinEndocrinol Metab. 2007; 92:405-413.

28

Laboratory Test ResultsLaboratory Test Results

Morning total testosterone: 160 ng/dLLH: lowProlactin: normalThyroid functions: normalLiver and kidney functions: normalLDL: 160Fasting glucose: 105CBC: normal

Morning total testosterone: 160 ng/dLLH: lowProlactin: normalThyroid functions: normalLiver and kidney functions: normalLDL: 160Fasting glucose: 105CBC: normalCBC = complete blood count; LDL = low-density lipoprotein.

29

What would be your next step?What would be your next step?

1. Prescribe testosterone

2. Prescribe PDE5 inhibitor

3. Prescribe testosterone + PDE5 inhibitor

4. Initiate weight loss program

5. Prescribe statin and oral hypoglycemic

1. Prescribe testosterone

2. Prescribe PDE5 inhibitor

3. Prescribe testosterone + PDE5 inhibitor

4. Initiate weight loss program

5. Prescribe statin and oral hypoglycemic

"Silent Killers" –Components of the metabolic syndrome

"Silent Killers" –Components of the metabolic syndrome

Dyslipidemia

Arterial Hypertension

Insulin Resistance /DM Type 2

+

Visceral fat tissue

BMI and BMI are not the same... Count on waist circumference

BMI and BMI are not the same... Count on waist circumference

189 cm, 93 kg = BMI 26 190 cm, 94 kg = BMI 26

Waist circumference Waist circumference>Testosterone Testosterone<

Guav AT J. Androl. 2009 Jul-Aug;30(4):370-6.Traish AM J. Androl. 2009b;302-23-32

There is an increased risk of hypogonadism in men with MS and its individual components, including insulin resistance.

Androgen Deficiency and Metabolic Androgen Deficiency and Metabolic Syndrome Share Many Common FactorsSyndrome Share Many Common Factors

Low Testosterone Levels are Associated with the Low Testosterone Levels are Associated with the Development of Metabolic SyndromeDevelopment of Metabolic Syndrome

In the MMAS, lower total T levels were predictive of metabolic syndrome, especially among those men with a body mass index below 25 kg/m2

Kupelian V et al. J Clin Endocrinol Metabl. 2006;91(3):843-850

Review of English-language literature re T and PCa

Number of articles in PSA era (1985-2004) regarding effect of TRT in men with PCa…

Review of English-language literature re T and PCa

Number of articles in PSA era (1985-2004) regarding effect of TRT in men with PCa…

Rhoden EL, Morgentaler R. N Engl J Med. 2004;350:482-492.

Number of Articles in PSA Era (1985-2004) Demonstrating TRT Causes PCa Progression…

Number of Articles in PSA Era (1985-2004) Demonstrating TRT Causes PCa Progression…

Testosterone and Prostate Cancer Prevalence

Prostate cancer risk doubled for men with the lowest testosterone values.

N=345aP=.04

Morgentaler A, Rhoden EL. Urology 2006;68(6):1263-1267

Is High T a Problem for PCa?Is High T a Problem for PCa?

Collaborative pooled worldwide analysis of 18 longitudinal studies

3886 men with PCa, 6438 controls

No association of PCa with serum androgensMen with PCa have similar T concentrations as men without PCa

Men with highest T at no greater risk of PCathan men with lowest T

Collaborative pooled worldwide analysis of 18 longitudinal studies

3886 men with PCa, 6438 controls

No association of PCa with serum androgensMen with PCa have similar T concentrations as men without PCa

Men with highest T at no greater risk of PCathan men with lowest T

RoddamRoddam AW, et al. AW, et al. J J NatlNatl Cancer InstCancer Inst. 2008;100:170. 2008;100:170--183.183.

38

Prostate Health AssessmentProstate Health AssessmentDRE

PSA

Consult with urologist

PSA >4.0 ng/mL

PSA velocity >0.4 ng/mL/y (using PSA level after 6 mo of therapy)

Detection of prostate abnormality on DRE

AUA prostate symptom score >19 with bother if PCP uncomfortable

DRE

PSA

Consult with urologist

PSA >4.0 ng/mL

PSA velocity >0.4 ng/mL/y (using PSA level after 6 mo of therapy)

Detection of prostate abnormality on DRE

AUA prostate symptom score >19 with bother if PCP uncomfortable

AUA = American Urological Association.Bhasin S et al. J Clin Endocrinol Metab. 2006;91:1995-2010.

39

Prostate Health Assessment Results

Prostate Health Assessment Results

IPSS: 11

DRE: normal

PSA: 0.7

IPSS: 11

DRE: normal

PSA: 0.7

IPSS = international prostate symptom score.

40

How would you counsel the patient?

How would you counsel the patient?

1. Testosterone therapy can be initiated safely

2. Referral to a urologist is necessary prior to testosterone therapy

3. Prostate biopsy will be necessary to rule out cancer

4. Consider alternatives to testosterone therapy

5. Not sure

1. Testosterone therapy can be initiated safely

2. Referral to a urologist is necessary prior to testosterone therapy

3. Prostate biopsy will be necessary to rule out cancer

4. Consider alternatives to testosterone therapy

5. Not sure

Effects of Testosterone Replacement in the Hypogonadal Man

Effects of Testosterone Replacement in the Hypogonadal Man

↑ Muscle strength/mass↑ Exercise tolerance

↑ Bone mineral density

↑ Mood/well-being↑ Cognition↑ Libido

↑ Erectile function↑ Sexual function

Effects on semen parameters

↓ CV risk factors

Improved CV profile

↓ Abdominal fat

↑ Insulin sensitivity

↑ Quality of life

↑ Erythropoeisis

Hair and beard effects

Skin effects

TRT improves insulin resistance, glycaemiccontrol, visceral adiposity and hyperlipidemia

in hypogonadal men with diabetes II

TRT improves insulin resistance, glycaemiccontrol, visceral adiposity and hyperlipidemia

in hypogonadal men with diabetes II

Double-blind placebo-controlled crossover study in 24 hypogonadal men over the age of 30 y with diabetes II.

Methods: IM testosterone 200 mg or placebo every 2 weeks for 3 months in random order, followed by a washout period of 1 month before the alternate treatment phase.

Double-blind placebo-controlled crossover study in 24 hypogonadal men over the age of 30 y with diabetes II.

Methods: IM testosterone 200 mg or placebo every 2 weeks for 3 months in random order, followed by a washout period of 1 month before the alternate treatment phase.

Kapoor D, Goodwin E, Channer KS & Jones TH: Euro J Endocrin 2006

3 mo Testosterone Treatment in 24 3 mo Testosterone Treatment in 24 HypogonadalHypogonadal Men Men (mean age: 64 yrs.) with Type 2 Diabetes Reduces HbA(mean age: 64 yrs.) with Type 2 Diabetes Reduces HbA1c1c ––

5 out of 10 Insulin5 out of 10 Insulin--Dependent Patients Reduced their Insulin Dependent Patients Reduced their Insulin Dosages Dosages

by a mean of 7 Unitsby a mean of 7 Units

Kapoor D et al. Eur J Endocrinol 154: 899-906 (2006)

p=0.03

3 mo Testosterone Treatment in 24 3 mo Testosterone Treatment in 24 HypogonadalHypogonadal Men (mean age: Men (mean age: 64 yrs.) with Type 2 Diabetes Reduces Waist Circumference and WH64 yrs.) with Type 2 Diabetes Reduces Waist Circumference and WHRR

a doublea double--blind, placeboblind, placebo--controlled, crossover studycontrolled, crossover study

Kapoor D et al. Eur J Endocrinol 154: 899-906 (2006)

p=0.03

p=0.01

WC WHR

45

Goals and Potential Benefits of Testosterone Replacement

Therapy

Goals and Potential Benefits of Testosterone Replacement

Therapy

Goals

●Treat signs and symptoms of hypogonadism

●Achieve and maintain eugonadalserum testosterone levels

●Individualize therapy to specific patient needs

Goals

●Treat signs and symptoms of hypogonadism

●Achieve and maintain eugonadalserum testosterone levels

●Individualize therapy to specific patient needs

Potential Benefits

●Restore libido and erectile function

●Increase energy and improve mood

●Improve body composition

↓ Fat mass

↑ Lean body mass

Possibly ↑ muscle strength

●Stabilize or increase BMD; perhaps reduce fractures

Potential Benefits

●Restore libido and erectile function

●Increase energy and improve mood

●Improve body composition

↓ Fat mass

↑ Lean body mass

Possibly ↑ muscle strength

●Stabilize or increase BMD; perhaps reduce fractures

Steidle CP. Rev Urol. 5(suppl 1):S34-S40; Nieschlag E, et al. Hum Reprod Update. 2004;10:409-419.

46

Options in Testosterone Replacement Therapy

Options in Testosterone Replacement Therapy

●IM: testosterone propionate, enanthate, or cypionate; testosterone undecanoate in development

●Buccal testosterone

●Transdermal patches

●Transdermal gel

●Oral: not approved in US

●Subcutaneous pellets

●IM: testosterone propionate, enanthate, or cypionate; testosterone undecanoate in development

●Buccal testosterone

●Transdermal patches

●Transdermal gel

●Oral: not approved in US

●Subcutaneous pellets Edelstein D, et al. Expert Opin Emerg Drugs. 2006;11:685-707.

48

Risks Associated With Testosterone Replacement Therapy

Risks Associated With Testosterone Replacement Therapy

COPD = chronic obstructive pulmonary disease

Wald M, et al. J Androl. 2006;27:126-132.

RISK COMMENT

• Oily skin, acne, skin reactions

Skin irritation more common with nonscrotal patches

• Breast enlargement or tenderness

Often transient and abates with continued treatment

• Sleep apnea?? Not reported as a consequence of treatment, but consider COPD in heavy smokers or overweight persons a relative contraindication

• Polycythemia Uncommon, but associated with age, sleep apnea, smoking history, and COPD

• Liver function abnormalities or tumors

Rare with injectable esters and transdermal formulations

• Lower extremity edema

May occur in first few months of treatment

• Symptomatic BPH and prostate cancer

Modest and inconsistent increases in prostate volume

Monitoring of Men Receiving TRT Monitoring of Men Receiving TRT Baseline

Determine voiding symptoms via history or IPSS

Determine history of sleep apnea

Digital rectal exam (DRE)

T levels, PSA, Hct, Hgb

Assess treatment efficacy at 1-2 mo; adjust dosage for suboptimal response

Evaluate patient at 3 mo and annually thereafter to assess symptom response and any adverse events

Baseline

Determine voiding symptoms via history or IPSS

Determine history of sleep apnea

Digital rectal exam (DRE)

T levels, PSA, Hct, Hgb

Assess treatment efficacy at 1-2 mo; adjust dosage for suboptimal response

Evaluate patient at 3 mo and annually thereafter to assess symptom response and any adverse events IPSS = International Prostate Symptom Score

Rhoden EL, Morgentaler A. N Engl J Med. 2004;350:482-492; Bhasin S, et al. J Clin Endocrinol Metab. 2006;91:1995-2010.

Monitoring of Men Receiving TRT(cont’d )

Monitoring of Men Receiving TRT(cont’d )

Check Hct and Hgb at 3 mo, then annually; if Hct>54%, stop therapy

Perform DRE and check PSA at 3-6 mo, then follow guidelines for screening (Q6month level, PSA, Hct, and DRE)

Measure BMD after 1-2 yr of therapy in men with osteoporosis

Evaluate formulation-specific adverse events at each visit

Check Hct and Hgb at 3 mo, then annually; if Hct>54%, stop therapy

Perform DRE and check PSA at 3-6 mo, then follow guidelines for screening (Q6month level, PSA, Hct, and DRE)

Measure BMD after 1-2 yr of therapy in men with osteoporosis

Evaluate formulation-specific adverse events at each visit IPSS = International Prostate Symptom Score

Rhoden EL, Morgentaler A. N Engl J Med. 2004;350:482-492; Bhasin S, et al. J Clin Endocrinol Metab.2006;91:1995-2010.

51

Testosterone FormulationsTestosterone Formulations

Formulation DosageInjectable

Testosterone cypionate/enanthate1,2

Testosterone undecanoate (TU)(in development in the United States)

50-400 mg every 2 wk750 mg at baseline, 4 wk, and every 10 wk thereafter

ImplantsTestosterone pellets4 150-450 mg (2-6 pellets) every 3-6 mo

TopicalTopical gel5,6

Transdermal patch system7

5-10 g daily5 mg daily

BuccalBuccal system8 30 mg every 12 h

1. Delatestryl [package insert]. Lexington, MA: Indevus Pharmaceuticals Inc; 2005. 2. Depo-Testosterone [package insert]. Kalamazoo, MI: Pharmacia Corporation; 2002. 3. Morgentaler A et al. J Urol. 2008;180:2307-

2313. 4. Testopel [package insert]. Rye, NY: Bartor Pharmacal Co Inc; 2007. 5. AndroGel [package insert]. Marietta, GA: Solvay Pharmaceuticals Inc; 2007. 6. Testim [package insert]. Norristown, PA: Auxilium

Pharmaceuticals Inc; 2003. 7. Androderm [package insert]. Corona, CA: Watson Pharma Inc; 2005. 8. Striant[package insert]. Livingston, NJ: Columbia Laboratories Inc; 2003.

52

Formulation-Specific Adverse EffectsFormulation-Specific Adverse Effects

Bhasin S et al. J Clin Endocrinol Metab. 2006;91:1995-2010.

Formulation Adverse EffectInjectable

Testosterone cypionate/enanthate Mood fluctuations or changes in libidoPain at injection siteErythrocytosis

TU (in development in the United States) Pain at injection site

ImplantsTestosterone pellets Potential infections or expulsion

TopicalTopical gel Skin-to-skin transferencePatch system Skin irritation

BuccalBuccal system Alterations in taste and irritation of gums and oral

mucosa

53

ConclusionsConclusionsHypogonadism and TRT

A symptom complex in the presence of low levels of testosterone

Age-related changes in physiologic function affected by testosterone levels

Hypogonadism is associated with significant reduction of quality of life, important comorbidities and maybe increased mortality

TRT in carefully selected patients provides satisfactory results

Expanding options for TRT

Hypogonadism and TRT

A symptom complex in the presence of low levels of testosterone

Age-related changes in physiologic function affected by testosterone levels

Hypogonadism is associated with significant reduction of quality of life, important comorbidities and maybe increased mortality

TRT in carefully selected patients provides satisfactory results

Expanding options for TRT

TRT = testosterone replacement therapy.