Male Hypogonadism and Testosterone therapy · Men with clinical symptoms and testosterone

Male Hypogonadism and Male Hypogonadism and

Testosterone therapyTestosterone therapy

Ketan DhatariyaKetan Dhatariya

Overview: Male HypogonadismOverview: Male Hypogonadism

Physiology of testosterone secretionPhysiology of testosterone secretion

Aetiology and clinical features Aetiology and clinical features

EpidemiologyEpidemiology

DiagnosisDiagnosis

Indications for treatmentIndications for treatment

Treatment optionsTreatment options

Monitoring Monitoring

ConclusionConclusion

Physiology of testosterone Physiology of testosterone

secretionsecretion

Testis structureTestis structure

TestosteroneSMOOTH

ENDOPLASMICRETICULUM

Cholesterol

Pregnenolone

Testosterone

Progesterone

17αααα-OH-Progesterone

Androstenedione

Testosterone

cAMP ATP

Cholesteryl

esters

LH

Cholesterol

P450scc

Pregnenolone

MITOCHONDRIA

Testosterone synthesis in the Leydig cell

17αααα-OH-Pregnenolone

DHEA

Androstenediol

3β-HSD

3β-HSD

3β-HSD

3β-HSD

17α-OH-lase17α-OH-lase

17,20 lyase17,20 lyase

17β-HSD17β-HSD

TestosteroneTestosterone

O

OH

Testosterone is the most important hormone Testosterone is the most important hormone

produced by the testisproduced by the testis

Between 5 and 7mg of testosterone are Between 5 and 7mg of testosterone are

produced by the Leydig cells daily in adult menproduced by the Leydig cells daily in adult men

Nieschlag E and Behre HM. Testosterone: action, deficiency, substitution (3rd Edition). Cambridge University Press, 2004

Hypothalamus

(Activin)

Regulation of Testicular FunctionRegulation of Testicular Function

GnRH

FSH

Oestradiol

Testosterone Inhibin B

LH

Leydig cells Sertoli cells

Interstitial cells

ENDOCRINE

Seminiferous tubules

EXOCRINE

Binding of TestosteroneBinding of Testosterone

T firmly bound T firmly bound

to SHBGto SHBG

60%60%

BIOAVAILABLE TESTOSTERONE BIOAVAILABLE TESTOSTERONE

= Albumin= Albumin--bound T + Free Tbound T + Free T

Free TFree TT loosely bound T loosely bound

to albuminto albumin

2%2%38%38%

Testosterone and its MetabolitesTestosterone and its Metabolites

Sexual differentiationMusculature

Bone massErythropoiesisPsychotropic actionPotency/libidoLipid metabolism

Bone massEpiphyseal closurePsychotropic actionLipid metabolismFeedback action

Prostate

Sexual differentiationSecondary hairSebum production

Prostate

Testosterone

Dihydrotestosterone Oestradiol

Aromatase

Aromatase

55ΩΩ-- Reduct

ase

Reductase

Hypogonadism: Aetiology and Hypogonadism: Aetiology and

Clinical FeaturesClinical Features

HypogonadismHypogonadism Hypogonadism is inadequate function of the Hypogonadism is inadequate function of the

testestestes

Prevalence: 5 men in 1000 in the UKPrevalence: 5 men in 1000 in the UK

22--4 million men in the US, estimated only 5% treated4 million men in the US, estimated only 5% treated

Diagnosis: clinical symptoms and biochemical Diagnosis: clinical symptoms and biochemical

teststests

PresentationPresentation

PrePre--pubertal: lack of secondary sexual development pubertal: lack of secondary sexual development

in teensin teens

PostPost--pubertal: insidious onset, features overlapping pubertal: insidious onset, features overlapping

with many systemic conditions, infertilitywith many systemic conditions, infertilityPetak SM et al. Endocrine Pract 2002;8:439-456. Nieschlag E et al. Eur Urol 2005;48:1-4. Handelsman DJ.

Androgens. In: Male reproductive endocrinology; Ed. Mclachlan RI. Endotext.com; 2002 Rhoden EL & Morgentaler A. NEJM 2004;350:482-92.

Clinical Picture of Testosterone Clinical Picture of Testosterone

DeficiencyDeficiency

•• Decreased muscle Decreased muscle

bulk/powerbulk/power

•• Abdominal obesityAbdominal obesity

•• Loss of libidoLoss of libido

•• Hot flushes/palpitationsHot flushes/palpitations

•• Decreased body hairDecreased body hair

•• AnaemiaAnaemia

•• SubfertilitySubfertility

•• Subnormal genital sizeSubnormal genital size

•• Loss of pubic hairLoss of pubic hair

•• Erectile dysfunctionErectile dysfunction

•• Sexual dysfunctionSexual dysfunction

•• DepressionDepression

•• Reduced wellReduced well--beingbeing

•• Low self esteemLow self esteem

•• Poor concentration/drivePoor concentration/drive

General body effectsGeneral body effects

Reproductive systemReproductive system

EmotionalEmotional ComplicationsComplications•• OsteoporosisOsteoporosis

•• Raised lipidsRaised lipids

•• Insulin resistanceInsulin resistance

•• SarcopaeniaSarcopaenia

Nieschlag E and Behre HM. Testosterone: action, deficiency, substitution (3rd Edition). Cambridge University Press; 2004.

Sex Hormones and HypogonadismSex Hormones and Hypogonadism

Jöckenhovel F. Male Hypogonadism. UNI-MED, Bremen; 2004.

LHLHFSHFSH

GnRHGnRH

HypothalamusHypothalamus

PituitaryPituitary

TestisTestis

SECONDARY SECONDARY

HYPOGONADISMHYPOGONADISM

Secondary testicular failure Secondary testicular failure

HypogonadotrophicHypogonadotrophic hypogonadismhypogonadism

PRIMARY HYPOGONADISM

Primary testicular failure

Hypergonadotrophic hypogonadism

Causes of Primary HypogonadismCauses of Primary Hypogonadism

CongenitalCongenital

Chromosomal defects e.g. Klinefelter's syndromeChromosomal defects e.g. Klinefelter's syndrome

Congenital Congenital anorchiaanorchia

Androgen receptor/enzyme defectsAndrogen receptor/enzyme defects

AcquiredAcquired

Testicular trauma/torsionTesticular trauma/torsion

Surgical removalSurgical removal

Chemotherapy/irradiationChemotherapy/irradiation

Complications of illnessComplications of illness

e.g. diabetes, renal failure, alcoholic liver disease, e.g. diabetes, renal failure, alcoholic liver disease,

cirrhosiscirrhosis Nieschlag E et al. Human Reprod Update 2004;10(5):409-419.

Causes of Secondary HypogonadismCauses of Secondary Hypogonadism CongenitalCongenital

KallmannKallmann’’ss syndromesyndrome

Idiopathic Idiopathic hypogonadotrophichypogonadotrophic hypogonadism (IHH)hypogonadism (IHH)

PraderPrader--Willi syndromeWilli syndrome

AcquiredAcquired

ProlactinomaProlactinoma

Pituitary adenomaPituitary adenoma

Hypothalamic tumourHypothalamic tumour

Anabolic steroid abuseAnabolic steroid abuse

Complications of illnessComplications of illness

e.g. AIDS, e.g. AIDS, haemochromatosishaemochromatosisNieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002.

Nieschlag E et al. Human Reproduct Update 2004;10(5):409-419.

LateLate--onset Hypogonadismonset Hypogonadism

A clinical and biochemical syndrome associated A clinical and biochemical syndrome associated

with advancing age and characterised by with advancing age and characterised by

typical symptoms and a deficiency in serum typical symptoms and a deficiency in serum

testosterone levelstestosterone levels

Nieschlag E et al. Eur Urology 2005;48:1-4.

Vermeulen A et al. J Clin Endocrinol Metab 1996;81:1821-1826.

SHBG Free T (x100) TestosteroneSHBG Free T (x100) Testosterone

0

25

50

75

25-34

(n=45)

35-44

(n=22)

45-54

(n=23)

55-64

(n=43)

65-74

(n=47)

75-84

(n=48)

75=100

(n=21)

Ho

rmo

ne level (n

mo

l/L

)

Age

EpidemiologyEpidemiology

Hypogonadism Incidence and Hypogonadism Incidence and

Age (US data)Age (US data)

0

5

10

15

20

25

Overall 48-59 60-69 70-79

Incid

ence

per

1,0

00 p

ers

on-y

ears

Age (years)

Expected 481,000 new cases p.a. in US men Expected 481,000 new cases p.a. in US men

4040--69 yrs69 yrs Araujo A et al. J Clin Endocrinol Metab 2004;89(12):5920-5926.

Low Testosterone and MortalityLow Testosterone and Mortality

0

10

20

30

40

50A

ll-C

ause M

ort

alit

y (

%)

Shores M et al. Arch Intern Med 2006;166:1660-166588% (88% (PP<0.001)<0.001)38% (38% (P P = 0.06)= 0.06)--

Increased Increased

mortality mortality

riskrisk

1.88 (1.341.88 (1.34--2.63)2.63)1.38 (0.991.38 (0.99--1.92)1.92)1.001.00Hazard Hazard

Ratio Ratio

(adjusted)(adjusted)

Low TLow T

(n=166)(n=166)

‘‘EquivocalEquivocal’’ T T

(n=240)(n=240)Normal T levels Normal T levels

(n=452)(n=452)

Mean fo

llow

-up

perio

d 4

.3 y

rs

Hypogonadism and CV risk Hypogonadism and CV risk

factorsfactors

Low testosterone levels in men frequently Low testosterone levels in men frequently

coco--exist withexist with

Type 2 diabetes mellitusType 2 diabetes mellitus

Erectile dysfunctionErectile dysfunction

Abdominal obesityAbdominal obesity

Other CV risk factorsOther CV risk factors

Component of the metabolic syndrome?Component of the metabolic syndrome?

CV, cardiovascular

Testosterone levels in type 2 Testosterone levels in type 2

diabetesdiabetes11

20 20 studiesstudies (total (total

n=3825 n=3825 menmen with with

diabetes)diabetes)11

1. Ding E et al. JAMA 2006;295:1288-1299.

Calculated mean Calculated mean

difference: difference: --2.66 nmol/l 2.66 nmol/l

(95% CI, (95% CI, --3.45 to 3.45 to --1.86) 1.86)

Testosterone levels in type 2 Testosterone levels in type 2

diabetesdiabetes11

16%

34%50%

T<7.5nmol/l

T 7.5-12nmol/l

T>12nmol/l

1. Kapoor D et al. Endocrine Soc Abstract Book 2004: 448.

300 UK men (mean age, 58 yrs) with 300 UK men (mean age, 58 yrs) with

type 2 diabetes type 2 diabetes

Testosterone

≤12 nmol/l

Prevalence of hypogonadism Prevalence of hypogonadism

in diabetesin diabetes

0

10

20

30

40

50

Free T Total T Bioavailable T

Perc

enta

ge o

f patients

1. Dhindsa S et al. J Clin Endocrinol Metab 2004; 89(11): 5462-5468.

n=103 men with type 2 diabetesn=103 men with type 2 diabetes

Prevalence of hypogonadism in Prevalence of hypogonadism in

EDED

n=2823 n=242

n=521 n=990

n=165

0

10

20

30

40

50

Bodie,

2003

Low,

2001

Guay,

2001

Guay,

1999

Martinez,

2006*

Perc

enta

ge o

f patients

with

hypog

ona

dis

m

Study:

1. Bodie J et al. J Urol 2003; 169:2262-2264.

2. Low WY et al. J Sex Med 2004;1, Suppl. 1:111.3. Guay AT et al. J Androl 2001;22(5):793-797.

4. Guay AT et al. Endocr Pract 1999;5(6): 314-321.

5. Martinez-Jabaloyas JM et al. BJU Int 2006;97:1278-1283. *Diagnosed from free testosterone level

Hypogonadism in diabetic vs Hypogonadism in diabetic vs

nondiabeticnondiabetic men with EDmen with ED11

22.3

34.0

All ages

ED no diabetes Diabetes

0

10

20

30

40

50

30-39 40-49 50-59 60-69 >70

Age (Years)

% H

yp

og

on

ad

ism

(T

<1

2n

mo

l/L

) p <0.0001

p <0.0001

1. Corona G et al. Eur Urol 2004; 46(2): 222-228.

n=1027 men with ED with and without type 2 diabetes mellitus

+ ED

0

4

8

12

16

20

24

<94cm 94 - 101.9cm 102cm≥

Waist circumference and Waist circumference and

testosterone leveltestosterone level11T

ota

l te

sto

ste

rone (

nm

ol/l)

1. Svartberg J et al. Europ J Epidemiol 2004;19:657-663.

Waist circumference (age-adjusted)

p =0.012

vs <94cm

The The TromsTromsøø Study: n=1548 Study: n=1548 communitycommunity--

dwellingdwelling menmen (age 25 (age 25 –– 84)84)11

--

(<37 inches) (37-40.1 inches) (≥40.2 inches)

Changes in body composition Changes in body composition

associated with androgen associated with androgen

deprivationdeprivation11

1. Smith MR et al. JCEM 2002;87:599-603.

n=32 men with non metastatic prostate cancer, treated with

leuprolide for 48 weeks. Serum testosterone levels fell by 96%.

-4

-2

0

2

4

6

8

10

12

% C

han

ge

2.4% 2.4%

9.4%

-2.7%

Weight* BMI*

Fat body mass**

Lean body mass**

*p=0.005 vs. baseline

**p<0.001 vs. baseline

1. Hypogonadism and Age1 2. Hypogonadism and Diabetes2

3. Hypogonadism and ED3-7 4. Low T and WaistCircumference8

Hypogonadism and CV risk Hypogonadism and CV risk

factorsfactors

1. Araujo A et al. J Clin Endocrinol Metab 2004;89(12):5920-5926. 2. Dhindsa S et al. J Clin Endocrinol Metab 2004; 89(11): 5462-5468. 3. Bodie J et al. J Urol 2003; 169:2262-2264. 4. Low WY et al. J Sex Med 2004;1, Suppl. 1:111. 5. Guay AT et al. J Androl 2001;22(5):793-797. 6. Guay AT et al. Endocr Pract 1999;5(6): 314-321. 7. Martinez-Jabaloyas JM et al. BJU Int 2006;97:1278-1283. 8. Svartberg J et al. Europ J Epidemiol 2004;19:657-663.

n=1087 n=103

n=1548

Diagnosing hypogonadismDiagnosing hypogonadism

Diagnosis of hypogonadismDiagnosis of hypogonadism11

Appropriate assessment of symptoms as Appropriate assessment of symptoms as

suggested by patientsuggested by patient’’s history and s history and

physical examinationphysical examination

Biochemical tests:Biochemical tests:

Total testosterone assayTotal testosterone assay

Gonadotrophins: LH/FSHGonadotrophins: LH/FSH

ProlactinProlactin

SHBG (can be used to calculate free SHBG (can be used to calculate free

testosterone)testosterone)1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer,

Heidelberg; 2002.

When should you measure When should you measure

testosterone?testosterone?11

Circadian rhythm of testosterone

1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer,

Heidelberg; 2002.

Patient history and physical examinationPatient history and physical examination

Measure serum testosterone levels between 7Measure serum testosterone levels between 7--11am11am

Patient presents with symptomsPatient presents with symptoms

T >12nmol/lT >12nmol/l

Consider alternative Consider alternative

diagnosesdiagnoses

T T ≤≤12nmol/l12nmol/l

Repeat T levelRepeat T level

Measure LH, FSH, Measure LH, FSH,

ProlactinProlactin

Repeat tests Repeat tests HYPOGONADISMHYPOGONADISM

T >12nmol/L, T >12nmol/L,

normal normal

Prolactin and Prolactin and

FSH/LHFSH/LH

T 8T 8--12nmol/L 12nmol/L

normal normal

Prolactin and Prolactin and

FSH/LHFSH/LH

T 8T 8--12nmol/L, 12nmol/L,

and and Prolactin Prolactin

or abnormal or abnormal

FSH/LHFSH/LH

T <8nmol/LT <8nmol/L

Patients with borderline Patients with borderline

testosterone levels (8testosterone levels (8--12 12

nmol/l)nmol/l)1,21,2

Consider additional biochemical testsConsider additional biochemical tests

Gonadotrophins, SHBG, prolactinGonadotrophins, SHBG, prolactin

Careful consideration of comorbiditiesCareful consideration of comorbidities

Calculate free testosterone Calculate free testosterone (see online (see online

calculator at calculator at

www.issam.ch/freetesto.htmwww.issam.ch/freetesto.htm))

Counsel patient regarding treatment Counsel patient regarding treatment

optionsoptions

1. Nieschlag E et al. Eur Urol 2005;48:1-4.

2. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.

Who should receive Who should receive

testosterone treatment? testosterone treatment? Men with clinical symptoms and Men with clinical symptoms and

testosterone <8 nmol/ltestosterone <8 nmol/l11

Men with clinical symptoms and Men with clinical symptoms and

testosterone 8testosterone 8--12 nmol/l where 12 nmol/l where

additional investigations indicate additional investigations indicate

presence of hypogonadismpresence of hypogonadism11

Older men with significant symptomsOlder men with significant symptoms

LongLong--term risks /benefits have yet to be term risks /benefits have yet to be

clearly demonstratedclearly demonstrated

Who should receive Who should receive

testosterone treatment? testosterone treatment? Contraindications to testosterone treatment

• Untreated or suspected carcinoma of prostate

• Moderate to severe symptoms of BPH

• Breast cancer

• Liver tumour

• Significant polycythaemia

• Severe cardiac failure

• Untreated sleep apnoea

15

12

10

8

0

Loss of libido p<0.001

Loss of vigour p<0.001

Obesity p<0.001

Feeling depressed p=0.001

Disturbed sleep p=0.004

Lack concentration p=0.002

Type 2 diabetes p<0.001

Hot flushes p<0.001

Erectile dysfunction p=0.003

N

84

65

67

75

Increasing prevalence of symptoms with

decreasing androgen concentrations

Zitzmann M et al. JCEM 2006;91:4335-4343

Total testosterone nmol/L

Treating hypogonadismTreating hypogonadism

Goals of testosterone Goals of testosterone

replacement therapyreplacement therapy1,21,2

Restore physiological testosterone levels Restore physiological testosterone levels

Alleviate symptoms of androgen Alleviate symptoms of androgen

deficiencydeficiency

Induce or restore physiological functionsInduce or restore physiological functions

Prevent longPrevent long--term health risks of term health risks of

androgen deficiencyandrogen deficiency



20

25

30

35

40

S 0 3 6 9 12 15 18 21 24 27 30

Testosterone therapy increases Testosterone therapy increases

testosterone levels and testosterone levels and

decreases SHBGdecreases SHBG11

Serum

testosterone (nmol/l)

(trough levels)

SHBG levels

(nmol/l)

Time (weeks)

Hypogonadal men Hypogonadal men

on IM on IM

testosterone testosterone

undecanoate undecanoate

(n=20) or IM (n=20) or IM


enanthate (n=20) enanthate (n=20)

for 30 weeksfor 30 weeks

1. Huebler D et al. Int J Impot Res 2002;12 (Suppl.):33 (Abstract).

0

10

20

30

Normal physiological range

Testosterone undecanoate

Testosterone enanthate

Testosterone therapy Testosterone therapy

significantly improves body significantly improves body

composition and BMDcomposition and BMD11

0

1

2

3

4

-2.5

-2

-1.5

-1

-0.5

0

0

0.01

0.02

0.03

0.04

0.05

0 6 18 30

Change in lean mass (Kg)

Change in fat mass (Kg)

Change in spine BMD

(g/cm2)

Time (months)

n=123 n=123

hypogonadal hypogonadal

men receiving men receiving

testosterone gel testosterone gel

5050--100mg/day 100mg/day

for 30 monthsfor 30 months

1. Adapted from Wang C et al. J Clin Endocrinol Metab 2004; 89:2085-2098.

Testosterone therapy improves Testosterone therapy improves

mood and sexual functionmood and sexual function11

0

1

2

3

4

No

spontaneous morning erections

No

ejaculations

Subjective change in

fatigue

Time (weeks)

Hypogonadal Hypogonadal

men on IM men on IM


undecanoate undecanoate

(n=20) for 30 (n=20) for 30

weeksweeks

1. Rouskova D. Schering Data on file, 6 May 2002..

0

1

2

3

4

0

20

40

60

0 3 6 9 12 15 18 21 24 27 30

Testosterone therapy reduces Testosterone therapy reduces

insulin resistance in insulin resistance in

hypogonadal diabetic menhypogonadal diabetic men11

1. Kapoor D et al. Eur J Endocrinol 2006;154:899-906.

HO

MA

in

de

x

*P=0.02, **P=0.003.

B) Mean (±SEM) change in HbA1c

0

1

2

3

4

5

6

Placebo Testosterone

*

0

1

2

3

4

5

6

Placebo Testosterone

*

Hb

A1

c (

%)

Baseline

3 Months

n=24

A) Mean (±SEM) change in HOMA index

Testosterone therapy improves Testosterone therapy improves

erectile function in hypogonadal erectile function in hypogonadal

men with EDmen with ED11

0

10

20

30

Erectile Function Sexual Desire

Baseline (n=122) Week 12 (n=71)

IIE

F S

core

1. Yassin A et al. World J Urol 2006; 24:639-644.

Effects of testosterone therapyEffects of testosterone therapy

EndocrineEndocrine

Increases testosterone Increases testosterone

Decreases SHBGDecreases SHBG

PhysicalPhysical

Body mass/muscle strength/BMDBody mass/muscle strength/BMD

Sexual functionSexual function

Morning erections, libido, sexual functionMorning erections, libido, sexual function

MoodMood

Improved mood and cognitive functionImproved mood and cognitive function

Treatment optionsTreatment options

Testosterone gelTestosterone gel200200

Testosterone patchTestosterone patch199199

88


55


22

Oral testosteroneOral testosterone197197

77

ShortShort--acting acting

injectable injectable

testosteronetestosterone

195195

44

Testosterone implantTestosterone implant194194

00

Oral testosterone Oral testosterone

(Restandol(Restandol®®;;AndriolAndriol®®/Testocaps/TestocapsTMTM))1,21,2

Tablets containing 40mg testosterone Tablets containing 40mg testosterone

undecanoate as a maintenance dose taken undecanoate as a maintenance dose taken

22--3 times a day3 times a day

Route of absorption is via lymphatic Route of absorption is via lymphatic

systemsystem

Therefore needs to taken with a meal Therefore needs to taken with a meal

containing dietary fatcontaining dietary fat

Without dietary fat absorption is minimal, and Without dietary fat absorption is minimal, and

pharmacokinetics unreliablepharmacokinetics unreliable1. Nieschlag E et al. Human Reproduct Update 2004; 10 (5):409-419.2. Organon Laboratories Limited. Restandol® SPC; May 1998.

Buccal testosteroneBuccal testosterone1,21,2

(Striant(Striant®®))

30mg testosterone tablet placed above 30mg testosterone tablet placed above

incisor tooth twice dailyincisor tooth twice daily

Avoids hepatic inactivationAvoids hepatic inactivation

Absorbed across oral mucosaAbsorbed across oral mucosa

Good pharmacokinetics, achieving normal Good pharmacokinetics, achieving normal

testosterone levelstestosterone levels

May be application difficultiesMay be application difficulties

Risk of site reactionsRisk of site reactions1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.

2. Ardana Bioscience. Striant® SPC; March 2005.

SubdermalSubdermal

(Testosterone implants)(Testosterone implants)

Testosterone pellets (100Testosterone pellets (100--600mg) 600mg)

implanted subdermallyimplanted subdermally22

Three to six pellets (600mg to 1.2g) usually Three to six pellets (600mg to 1.2g) usually

maintain plasma testosterone concentrations maintain plasma testosterone concentrations

for 4for 4--6 months6 months11

Risk of supraphysiological testosterone Risk of supraphysiological testosterone

levelslevels

Minor surgical procedureMinor surgical procedure

Can be painful/infection risk/scarringCan be painful/infection risk/scarring

8.5% extrusion of pellets8.5% extrusion of pellets33

1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.

2. Organon Laboratories Limited. Testosterone Implant 200mg SPC; May 1999.3. Handelsman DJ et al. Clin Endocrinol 1997;47:311-316.

Transdermal patchesTransdermal patches1,21,2

(e.g. Andropatch(e.g. Andropatch®®))

2.52.5--7.5mg testosterone delivered, 7.5mg testosterone delivered,

starting dose starting dose

Daily circadian profile of testosterone Daily circadian profile of testosterone

deliverydelivery3,43,4

Alcohol base to enhance permeation Alcohol base to enhance permeation

Skin reactions common (>50% Skin reactions common (>50%

patients)patients)3,43,4

Size of patch can be obtrusiveSize of patch can be obtrusive

May make crinkling noiseMay make crinkling noise


2. GlaxoSmithKline UK. Andropatch® 5mg SPC; August 2002.

3. Wang C et al. J Clin Endocrinol Metab 2000; 85(8):2839-2653.

4. Gooren LJG et al. Drugs 2004.64(17):1861-1891.

Transdermal gelsTransdermal gels1,2,31,2,3

(Testogel(Testogel®®; Testim; Testim®®))

5050--100 mg testosterone gel applied each 100 mg testosterone gel applied each

morning to shoulders, back, or abdomenmorning to shoulders, back, or abdomen

Daily circadian profile of testosterone Daily circadian profile of testosterone

deliverydelivery2,42,4

Skin reactions in 4Skin reactions in 4--10% patients10% patients2,32,3

Avoid washing for 6 hoursAvoid washing for 6 hours

Risk of transfer to another person via skin Risk of transfer to another person via skin

contactcontact

Daily patient compliance requiredDaily patient compliance required


2. Schering Health Care Limited. Testogel ® 50mg SPC; February 2004.

3. Ipsen Ltd. Testim ® 50mg SPC; August 2004.4. Wang C et al. J Clin Endocrinol Metab 2000; 85(8):2839-2653.

Intramuscular injections Intramuscular injections -- short short

actingacting1,21,2

(Sustanon(Sustanon®® 100; Sustanon100; Sustanon®®

250; 250; TestovironTestoviron®®)) Currently the most widely used form of Currently the most widely used form of

testosteronetestosterone

Two shortTwo short--acting preparations widely available acting preparations widely available

in UKin UK

Sustanon 100 (testosterone: Sustanon 100 (testosterone:

propionate/propionate/phenylpropionatephenylpropionate/ isocaproate in / isocaproate in arachisarachis

oil)oil)

Sustanon 250 (testosterone: Sustanon 250 (testosterone:

propionate/propionate/phenylpropionatephenylpropionate/ isocaproate/decanoate / isocaproate/decanoate

in in arachisarachis oil)oil)

Injection every 2 weeks (Sustanon 100) or 3 Injection every 2 weeks (Sustanon 100) or 3

weeks (Sustanon 250)weeks (Sustanon 250)2,32,3

Peak and trough testosterone levelsPeak and trough testosterone levels

1 Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.

2. Organon Laboratories Limited. Sustanon® 100 SPC; February 2004

3. Organon Laboratories Limited. Sustanon® 250 SPC; January 2006.

Intramuscular injections Intramuscular injections -- long long

actingacting11

(Nebido(Nebido®®)) 1000 mg testosterone undecanoate in 4 1000 mg testosterone undecanoate in 4

ml castor oil ml castor oil

Loading dose at 6 weeks, and then every Loading dose at 6 weeks, and then every

10 to 14 weeks10 to 14 weeks11

Testosterone levels maintained within the Testosterone levels maintained within the

physiological rangephysiological range22

Avoids frequent peaks and troughs in Avoids frequent peaks and troughs in

testosterone levels that may be seen with testosterone levels that may be seen with

shortshort--acting injectionsacting injections33

Increased patient convenience (quarterly Increased patient convenience (quarterly

1. Schering Health Care Limited. Nebido ® SPC; October 2004.

2.Von Eckardstein S et al. J Androl 2002;23(3):419-425.3.Schubert M et al. J Clin Endocrinol Metab 2004;89:5429-5434.

Testosterone therapyTestosterone therapy

Number of testosterone preparations Number of testosterone preparations

availableavailable

Differ by route of applicationDiffer by route of application

Patient choice and satisfaction importantPatient choice and satisfaction important

Patients should be provided with sufficient Patients should be provided with sufficient

information to enable them to make an information to enable them to make an

informed decision regarding suitable informed decision regarding suitable

therapytherapy

Pharmacokinetics of different Pharmacokinetics of different

testosterone preparationstestosterone preparations

Pharmacokinetics: daily Pharmacokinetics: daily

testosterone preparationstestosterone preparations11


50

40

30

20

10

Note the different timescales on these graphs

Pharmacokinetics of UK available Pharmacokinetics of UK available

injectable testosterone injectable testosterone

preparations: Sustanon 250preparations: Sustanon 25011

1. Lane HA et al. Endocrine Abstracts 2006;11:P677.

0

10

20

30

40

1 2 3 4

Sustanon 250

Weeks

0

10

20

30

40

0 1 2 3 4 5 6 7 8 9 10 11 12Weeks

Se

rum

te

sto

ste

ron

e (

nm

ol/L

)

T undecanoate (1st injection)

T undecanoate (13th injection)

Pharmacokinetics of UK available Pharmacokinetics of UK available

injectable testosterone injectable testosterone

preparations: Nebidopreparations: Nebido11--33

1. Von Eckardstein S et al. J Androl 2002; 23(3):419-425.

2. Behre HM et al. Eur J Endocrinol 1999;140:414-419.

Data are from 2 separate

studies, i.e. not a

comparative trial

Pharmacokinetics: Injectable Pharmacokinetics: Injectable

testosterone preparationstestosterone preparations1,21,2


2. Von Eckardstein S et al. J Androl 2002; 23(3):419-425.

0

10

20

30

40

50

0 3 6 9 12

0

10

20

30

40

WeeksWeeks

Testosterone Testosterone

undecanoateundecanoate

Testosterone enanthate*Testosterone enanthate*

*Simulated data

Pharmacokinetics: testosterone Pharmacokinetics: testosterone

implantsimplants

1. Jockenhovel F et al. Clin Endo 1996;45:61-71.

Monitoring patients on Monitoring patients on

testosterone therapytestosterone therapy

Areas of potential concernAreas of potential concern1,21,2

ProstateProstate

CardiovascularCardiovascular

Behavioural changesBehavioural changes

Personality changesPersonality changes



Parameters to monitor or to be Parameters to monitor or to be

aware of during therapyaware of during therapy1,21,2

ProstateProstate

Haematocrit and haemoglobinHaematocrit and haemoglobin

Increased levels particularly associated with Increased levels particularly associated with

supraphysiological levels of testosteronesupraphysiological levels of testosterone

Blood lipidsBlood lipids

Liver functionLiver function

Miscellaneous adverse effects of Miscellaneous adverse effects of


E.g. gynaecomastia, acne, oily skin, priapism, E.g. gynaecomastia, acne, oily skin, priapism,

sleep apnoeasleep apnoea

1. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010. 2. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.

Endocrine Society: Endocrine Society:

recommendationsrecommendations11

YY

--

YY

YY

YY

BaselineBaseline

--

YY

YY

YY

YY

3 month3 month

YYBMDBMD

YYTestosteronTestosteron

ee

YYHaematocritHaematocrit

YYDREDRE

YYPSAPSA

AnnualAnnualParametParamet

erer


PSA levelsPSA levels

PSA = screening test for prostate cancerPSA = screening test for prostate cancer

PSA increases with agePSA increases with age

Increase in accepted PSA cutIncrease in accepted PSA cut--off with ageoff with age

4040--49 years 49 years 2.5 2.5 ngng/ml /ml



Over 70 years Over 70 years 6.5 6.5 ngng/ml /ml

Endocrine Society: Prostate Endocrine Society: Prostate

monitoringmonitoring11

Urological consultation should be sought if Urological consultation should be sought if

there is:there is:

Verified PSA >4.0 Verified PSA >4.0 ngng/ml/ml

Increase in PSA concentration >1.4ng/ml Increase in PSA concentration >1.4ng/ml

within any 12within any 12--month period of testosterone month period of testosterone

treatmenttreatment

PSA velocity >0.4ng/ml/year PSA velocity >0.4ng/ml/year

Detection of a prostatic abnormality on DREDetection of a prostatic abnormality on DRE


0

5

10

15

20

25

0 12 30 0 12 30

Weeks

Prostate Volume (ml)

18.2417.16

14.29 14.51

19.8420.75

1. Huebler D et al. Endo 2000 Abstract Book: 567.

PSA and prostate volume during PSA and prostate volume during

testosterone treatmenttestosterone treatment

Weeks

PSA (µg/l)

0

0.25

0.5

0.75

1

-3 0 3 6 9 12 15 18 21 24 27 30

T enanthate T undecanoate

14

15

16

S 0 3 6 9 12 15 18 21 24 27 30

Haemoglobin (g/dl)

Weeks

Haematocrit (%)

Weeks

42

44

46

48

S 0 3 6 9 12 15 18 21 24 27 30

1. Huebler D et al. Endo 2000 Abstract Book: 567.

ErythropoiesisErythropoiesis under under

testosterone treatment in 40 testosterone treatment in 40

hypogonadal menhypogonadal men

T enanthate T undecanoate

Conclusion (1)Conclusion (1)

Testosterone influences sexual, Testosterone influences sexual,

metabolic and psychological functionsmetabolic and psychological functions

Male hypogonadism is inadequate Male hypogonadism is inadequate

functioning of the testes, characterised functioning of the testes, characterised

by abnormally low testosterone levelsby abnormally low testosterone levels

Male hypogonadism is associated with Male hypogonadism is associated with

increasing age, ED, type 2 diabetes and increasing age, ED, type 2 diabetes and

abdominal obesityabdominal obesity

Diagnosis of hypogonadism is based on Diagnosis of hypogonadism is based on

clinical features with biochemical clinical features with biochemical

confirmationconfirmation

Conclusion (2)Conclusion (2)

Testosterone therapy increases circulating Testosterone therapy increases circulating

testosterone levels with significant testosterone levels with significant

symptom improvementsymptom improvement

Treatment decision based on compliance, Treatment decision based on compliance,

convenience, choiceconvenience, choice

Monitor: prostate/haematocrit/clinical Monitor: prostate/haematocrit/clinical

responseresponse

Testosterone therapy provides significant Testosterone therapy provides significant

improvement in quality of life for patients improvement in quality of life for patients

with male hypogonadismwith male hypogonadism

NEBIDO PRESCRIBING INFORMATION 1Nebido (testosterone undecanoate)Presentation: Ampoule with 4ml solution for injection containing 1000mg testosterone undecanoate. Uses: Testosterone replacement therapy for male hypogonadism when testosterone deficiency confirmed by clinical features and biochemical tests.Dosage: One ampoule (1000mg) injected intramuscularly every 10 to 14 weeks. Starting treatment: Measure serum testosterone levels before start and during initiation of treatment. If appropriate, first injection interval may be reduced to a minimum of 6 weeks. Maintenance: Injection interval within 10 to 14 week range. Monitor serum testosterone regularly; adjust injection interval as appropriate.Children: Not for use in children. Not evaluated clinically in males under 18.Contra-indications: Androgen-dependent prostate cancer or breast cancer. Past or present liver tumours. Hypersensitivity to testosterone or any of the excipients.Warnings and precautions: Limited experience in patients over 65. Before therapy exclude prostate cancer. Examine prostate and breast at least annually, or twice yearly in elderly or at risk patients (clinical or familial factors). Periodically check testosterone concentrations, haemoglobin, haematocrit, liver function. Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostatic hyperplasia. Monitor serum calcium concentrations in cancer patients at risk of hypercalcaemia (and hypercalcinuria). Rarely, liver tumours have been reported.Nebido may cause oedema with or without congestive cardiac failure in patients with severe cardiac, hepatic or renal insufficiency or ischaemic heart disease. In this case, stop treatment immediately. Use with caution in patients with renal or hepatic impairment, epilepsy, migraine or blood clotting irregularities. Improved insulin sensitivity may occur.Irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dose adjustment. Withdraw treatment if these symptoms persist or reappear. Pre-existing sleep apnoea may be potentiated.Testosterone may produce a positive reaction in anti-doping tests. Not for use in women. Not suitable for developing muscles or increasing fitness in healthy individuals. Inject Nebido extremely slowly to avoid the coughing or respiratory distress reactions that occur rarely with injection of oily solutions.Interactions reported with oral anticoagulants (requires dose monitoring), ACTH or corticosteroids, and thyroxin binding globulin in laboratory tests.

NEBIDO PRESCRIBING INFORMATION 2

Side-effects: Most common reactions are injection site pain (10%). Also reported are: diarrhoea; leg, breast or testicular pain; arthralgia; dizziness; increased sweating; headache; respiratory, skin or prostate disorders; acne; gynaecomastia; pruritus; subcutaneous haematoma at injection site. Other known reactions to testosterone containing preparations are: polycythaemia (erythrocytosis); weight

gain; electrolyte changes; muscle cramps; nervousness, hostility, depression; sleep apnoea; very rarely jaundice and liver function test abnormalities; skin reactions; libido changes; increased frequency of erections; interruption or reduction in spermatogenesis; priapism; prostate abnormalities; prostate cancer (inconclusive data); urinary obstruction; water retention; oedema; hypersensitivity. Basic NHS Price: £76.70 per 1 x 4mlLegal Classification: POMProduct Licence Number: 0053/0350Product Licence Holder: Schering Health Care Ltd.,

The Brow,Burgess Hill,West Sussex RH15 9NE

Nebido is a registered trademark of Bayer Schering Pharma AG (formerly Schering AG)PI revised: 28 June 2007

Information about adverse reaction reporting in the UK can be found at www.yellowcard.gov.uk. Alternatively, adverse reactions can be reported to Bayer plc by email: [email protected]

TESTOGEL PRESCRIBING INFORMATION 1

Testogel (testosterone)Presentation: Sachet containing 50mg testosterone in 5g colourless gel.Uses: Testosterone replacement therapy for male hypogonadism when testosterone deficiency confirmed by clinical features and biochemical tests.Dosage: One 5g gel sachet daily. Can be adjusted in 2.5g gel steps, to a maximum of 10g gel daily. Once sachet opened, apply immediately onto clean, dry healthy skin over both shoulders, or both arms or abdomen. Do not apply to genital areas.Children: Not for use in children. Not evaluated clinically in males under 18.Contra-indications: Known or suspected prostate or breast cancer. Hypersensitivity to testosterone or any constituents of the gel.Warnings and precautions: Before therapy exclude prostate cancer. Examine prostate and breast at least annually, or twice yearly in elderly or at risk patients (clinical or familial factors). Monitor serum calcium concentrations in cancer patients at risk of hypercalcaemia (and hypercalcinuria).Testogel may cause oedema with or without congestive cardiac failure in patients with severe cardiac, hepatic or renal insufficiency. In this case, stop treatment immediately. Use with caution in patients with ischaemic heart disease, hypertension, epilepsy and migraine. Periodically check testosterone concentrations, haemoglobin, haematocrit, liver function (tests), lipid profile.Possible increased risk of sleep apnoea especially if obesity or chronic respiratory disease present. Improved insulin sensitivity may occur.Irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dose adjustment.If severe application site reactions occur, discontinue if necessary. Testosterone may produce a positive reaction in anti-doping tests. Not for use in women.Testosterone gel can be transferred to others by close skin to skin contact and can lead to adverse effects (inadvertent androgenisation) if repeated contact. Inform patient of transfer risk that is prevented by clothing or washing of application site. Testogel should not be prescribed for patients who may not comply with safety instructions (e.g. alcoholics, drug abusers, psychiatric patients). Pregnant women must avoid any contact with the application sites. Interactions reported with oral anticoagulants, ACTH or corticosteroids, and thyroxin binding globulin in laboratory tests.

TESTOGEL PRESCRIBING INFORMATION 2Side-effects: Most common (10%) were: skin reactions. Also reported were: changes in

laboratory tests (polycythaemia, lipids), headache, prostatic disorders, gynaecomastia, mastodynia, dizziness, paraesthesia, amnesia, hyperaesthesia, mood disorders, hypertension, diarrhoea, alopecia, urticaria. Other known reactions to testosterone treatments are: muscle cramps; nervousness; depression; hostility; sleep apnoea; skin reactions; libido changes; more frequent erections; hypersensitivity reactions; rarely: jaundice, liver function tests, priapism, prostate

abnormalities, prostate cancer (inconclusive), urinary obstruction. During high dose and/or prolonged treatment: weight gain, electrolyte changes, reversible interruption or reduction of spermatogenesis, water retention, oedema, rarely hepatic neoplasms. Frequent applications may cause irritation and dry skin.

Basic NHS Price: £33.00 per pack of 30 x 5g sachetsLegal Classification: POMProduct Licence Number: 16468/0005Product Licence Holder: Laboratoires BESINS INTERNATIONAL5, rue du Bourg L’Abbé75003 ParisFranceDistributed by: Schering Health Care Ltd.,

The Brow,Burgess Hill,

West Sussex RH15 9NETestogel is a registered trademark of Laboratoires BESINS INTERNATIONALPI revised: 4 July 2007

Information about adverse reaction reporting in the UK Information about adverse reaction reporting in the UK

can be found at can be found at www.yellowcard.gov.ukwww.yellowcard.gov.uk. Alternatively, . Alternatively,

adverse reactions can be reported to Bayer plcadverse reactions can be reported to Bayer plc by by

email:email: [email protected]@bayer.co.uk

Male Hypogonadism and Testosterone therapy · Men with clinical symptoms and testosterone

Documents

Transcript of Male Hypogonadism and Testosterone therapy · Men with clinical symptoms and testosterone