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Hypogonadism- an overview -

Slide Set Version 1

Supported by an educational grant from Schering AGWriting and editing by Thomson Physicians World GmbH

What is hypogonadism?

Male hypogonadism can be defined as inadequate function of the testes in man:

• Reduced or absent synthesis and secretionof androgens (e.g. testosterone)

• Reduced or absent production of non-steroidal hormones (inhibin, activin) influencing the dynamic feedback controlsystem to both hypothalamus and hypophysis

Jockenhövel F: Male hypogonadism. UNI_MED Verlag Bremen 2004

Regulation of testicular function

Inhibin

Adipose tissue

TestosteroneEstradiol

NA+± ±±GABA ±

Endo-

DA ±Serum LevelsGnRH

+

FSH LHLH

FSH

-

Testis0 6 12 18 24

Time

Testosterone

-

+ +

GnRH



Male hypogonadism - classification

Hypogonadism

Primary

hypogonadism

Secondary

hypogonadism

Target organ

resistance

• Feminisation due to androgen resistance or5-alpha-reductase deficiency

• Estrogen deficit due to aromatase deficiency

Age-related

hypogonadism

• Late onset hypo-

gonadism

Testicular causes

• Klinefelter syndrome

• Orchitis

• Congenital or acquired

anorchia

• Testicular maldescent

• Testicular tumor

Hypothalamic causes

• Idiopathic hypogonado-

tropic hypogonadism

• Kallmann syndrome

• Constitutional delay of

growth and development

Pituitary causes

• Hypopituitarism

• Pituitary tumors

Primary hypogonadism

• In male primary hypogonadism, the testes themselves do not function properly1

• The production of endocrine and paracrinehormones necessary for sexual differentiation in utero is decreased

• Primary hypogonadism is characterised by reducedblood levels of testosterone with elevated LH and FSH levels

• Some causes of primary hypogonadism includesurgery, radiation, genetic and developmentaldisorders, liver and kidney disease, infection and certain autoimmune disorders1

1http://www.nlm.nih.gov/medlineplus/ency/article/001195.htmJockenhövel F: Male hypogonadism. UNI_MED Verlag Bremen 2004

Secondary hypogonadism

• The cause of secondary / hypogonadotropichypogonadism lies in the pituitary gland

• Impaired testicular function as a consequence of hypothalamic or pituitary disorders

• Characterised by reduced blood levels of testosterone (T) associated with low or normal levels of LH and FSH

• Can be caused by trauma, radiation or infarction

• Can be a systemic or genetic disorder

Jockenhövel F: Male hypogonadism. UNI_MED Verlag Bremen 2004Bagatell CJ and Bremner WJ, N Engl J Med 1996;334:707-714Nieschlag E in: Nieschlag E and Behre HM (eds), Andrology, 2nd edn Springer Berlin, 2000; pp 83-88

Late-onset hypogonadism (LOH)

Age-associated decrease in androgenproduction

• Between the ages of 40 and 70, total and freeserum T decrease by approx. 1.2% per year

• 12% of men over 50 years of age and almost 50% of men above the age of 80 have low serum total T levels1

• 9.4% of men aged 60-70 years are diagnosed withclinical hypogonadism2

• In contrast to the cessation of gonadal function in menopause, the decrease of serum T is gradual

1Harman SM et al., J Clin Endocrinol Metab 2001;86(2):724-312Araujo AB et al., J Clin Endocrinol Metab 2004;89(12):5920-6Jockenhövel F: Male hypogonadism. UNI_MED Verlag Bremen 2004

Endocrine changes with age

Vermeulen A, Ann Med 1993;25:531

Free T (nmol/l) SHBG (10-8 mol/l) Total T (nmol/l)

Age (years)

Total T

Free T

SHBG

0

5

10

15

20

25

crude 40-49 50-59 60-70 crude 48-59 60-69 70-79

%

Baseline (n=1.691)Follow-up (n=1.087)

10 years later

Crude and age-specific prevalence of androgendeficiency at baseline and follow-up in theMassachusetts Male Aging Study (MMAS)

Araujo AB et al., J Clin Endocrinol Metab 2004;89(12):5920-5926

Testosterone deficiency and age

1Harman SM et al., J Clin Endocrinol Metab 2001;86 (2):724-731

Total testosterone (cut-offvalue 11.3 nmol/l1)

Free testosterone index (cut-off value 0.153 nmol/l)

Perc

ent

Age (years)

Testosterone

Dihydrotestosterone5α-Reductase

• Sex. differentiation• Muscle mass• Bone mass• Bone marrow• Erythropoietin product• Psychotropic effect• Erectile function

• Sex. differentiation• Body hair• Sebum production• Prostate size and

function

• Bone mass• Epiphysis closure• Psychotropic effect• Feedback on pituitary• Prostate size and

function

Estradiol

Aromatase

Direct and indirect effects of testosterone in men


Symptoms of male hypogonadism

• Diminished sexual desire, erectile quality and frequency, particularly nocturnal erections

• Changes in mood with concomitant decreases in intellectualactivity, cognitive functions, spatial orientation ability, fatigue, depressed mood and irritability

• Sleep disturbances

• Decrease in lean body mass with associated diminution in muscle volume and strength

• Increase in visceral fat

• Decrease in body hair, onset of skin alterations?

• Decrease in bone mineral density

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

Diagostics

Laboratory diagnostics

• Total serum testosterone (T) and sex hormonebinding globulin (SHBG) between 7:00 a.m. and 11:00 a.m.

• Calculation of free T (if not determined byequilibrium dialysis)*

• T therapy may be required if: – Total T levels are below 12 nmol/l (346 ng/dl)

– Free T levels are below 250 pmol/l (72 pg/ml)

Nieschlag E et al., Eur Urol 2005;48:1-4*http://www.issam.ch/freetesto.htm

Diagnosis- and Treatment Algorithm for LOH

Subnormal (<8 nmol/l)

Measurement T, LH, FSH, PRLConfirmation low total or free T

High concentrationof Gonadotropins

No contraindications

T treatment

Surveillanceof reaction

Check diagnosis

Gonadotropins at lower normal level

Check function of pituitary gland and

possible other reasons

Treatment of underlying disease, evtl. T substitution

Calculation free T through SHBG

Borderline(8-12 nmol/l)

Subnormal (<180 pmol/l)

Normal (>250 pmol/l)

No androgendeficiency.Search for

other reasons

No androgendeficiency. Searchfor other reasons

Normal (>12 nmol/l)

Reference range for young menTotal T: 12-35 nmol/l; calculated free T 250-850 pmol/l

Based on the ISA, ISSAM and EAU 2005 recommendations

• Muscle (-), fat (+) •Libido (-), erectile dysfunction

• Drive/impulse (-), fatigue, depressive mood

Measurement total T and SHBG (before noon)

Symptoms

Contraindications of testosterone therapy

Absolute contraindications• Suspected or diagnosed carcinoma of the prostate or breast.• Significant polycythemia, untreated sleep apnea, severe heart

failure, severe symptoms of lower urinary tract obstruction orclinical findings of bladder outflow obstruction due to benignprostate hypertrophy.

Partial contraindications• Moderate urinary obstruction (contraindication lifted after

successful treatment)

► In the absence of definite contraindications, age as such isnot a contraindication to initiate testosterone substitution.


Treatment and monitoring

Mandatory in men over the age of 45:• Baseline assessment of prostate health

– Prior to starting T therapy– At quarterly intervals for the first 12 months– Thereafter at yearly intervals

• Periodic haematological assessment, i.e. before treatment, every 3 months for one year and thereafter annually.

• Digital rectal examination (DRE) and determination of serumprostate-specific antigen (PSA) – Mandatory in men over the age of 45 prior to T therapy– Should be performed at quarterly intervals for the first 12 months

and yearly thereafter. – If DRE or serum PSA levels are abnormal, transrectal

ultrasound-guided biopsies of the prostate are indicatedNieschlag E et al., Eur Urol 2005;48:1-4

The role of testosterone in themetabolic syndrome

European Study Group for the Study of Insulin Resistance (EGIR), Diabet Med 1999;16:442-443Makhsida N et al., J Urol 2005;174:827-834

WHO definition of the metabolic syndromein men

• Hyperinsulinemia (upper quartile of the nondiabeticpopulation) or fasting plasma glucose ≥ 110 mg/dl

AND at least 2 of the following:

• Abdominal obesity– definition 1: waist-hip ratio > 0.90 or BMI ≥ 30– definition 2: waist girth ≥ 94 cm

• Dyslipidaemia (serum triglycerides ≥ 150 mg/dl or HDL cholesterol < 35 mg /dl)

• Hypertension (blood pressure ≥ 140/90 mmHg or medication)• Urinary albumin excretion rate ≥ 20 µg/min or

albumin/creatinin ratio ≥ 30 mg/g

Testosterone and the metabolic syndrome

• Today (2005) low T levels are considered a component of the metabolic syndrome

• Hypogonadism, obesity and insulin resistance maybe regarded as sentinel factors in the developmentof the metabolic syndrome

• T has beneficial effects on body mass composition, insulin sensitivity and blood pressure regulation, all factors of the metabolic syndrome

• However, T as a treatment for metabolic syndromehas not been thoroughly studied

• Future definitions of the metabolic syndrome mightinclude hypogonadism as a diagnostic parameter

Makhsida N et al., J Urol 2005;174:827-834

Hypogonadism in patients withDiabetes mellitus

• Hypogonadism is highly prevalent amongdiabetic men

• At the present time, the effect of T on bloodsugar and insulin sensitivity is unclear

• Diabetes mellitus should be evaluated and treated before or simultaneously with T substitution until positive effects of T on blood sugar control are definitively demonstrated


• Reference range

Svartberg J et al., Eur J Endocrinol 2004;150:65-71

n = 1548 men, aged 25 – 84 * p < 0.001

*

Waist circumference and testosterone levels in community dwelling men - the Tromsø study

0

4

8

12

16

20

24

< 94 94 – 101.9 >/= 102Waist circumference in cm

Tota

l tes

tost

eron

ein

nm

ol/l

*age- and BMI-adjusted

Association of endogenous testosterone with blood pressure in 1548 men participating in the Tromsø study

Svartberg J et al., Eur J Endocrinol 2004;150:65-71

02468

1012141618

25-39 40-49 50-59 60-69 70-840

50

100

150

200

250

300

25-39 40-49 50-59 60-69 70-84

p<0.001*

No hypertension (SBP<140 and DBP<90)

Hypertension

Tota

l T (n

mol

/l)

p=0.035*

Age groups (years)

Free

T (p

mol

/l)

Perc

ent b

ody

fat

(per

cent

of b

asel

ine)

Time (months)

0 6 12 18

100

95

90

85

80

Katznelson L et al., J Clin Endocrinol Metab 1996;81(12):4358-4365

Changes in percent body fat in hypogonadal men receiving 100 mg testosterone enanthate (TE) per week

0

5

10

15

20

25

30

0

20

40

60

80

100

120p < 0.001

p < 0.01

p < 0.001

p < 0.001

p < 0.01

T (ng/ml) Free T(pg/ml)

Fasting insulin(µU/ml)

HOMA* Fasting glucose(mg/dl)

Hypogonadal Overweight/obese Normal weight

Hormone and metabolic parametersin hypogonadal, obese and control male subjects

*Homeostasis model assessment

Pagotto U et al., J Clin Endocrinol Metab 2003;88(9):4139-4143

Hormone and metabolic parameters in hypogonadal male subjects after testosterone treatment

Pagotto U et al., J Clin Endocrinol Metab 2003;88(9):4139-4143

0

5

10

15

20

25

85

90

95

100

p < 0.01

p < 0.05

p < 0.05

NS

p < 0.05

T (ng/ml) Free T(pg/ml)

Fasting insulin(µU/ml)

HOMA*

before after

Fasting glucose(mg/dl)

*Homeostasis model assessment

Page ST et al., J Clin Endocrinol Metab 2005;90(3):1502-1510

Testosterone reduces total cholesterolin 70 elderly men

160

180

200

220

p<0.01

Testosterone Placebo

Tota

l cho

lest

erol

(mg/

dl) baseline

12 months36 months

(Mean age 71, T< 12.1 nmol/l)

Kapoor D et al., Endocrine Soc Abstract Book 2004;448

10

15

20

25

30

35

40

45

50

55

%

Total T < 7.5 nmol/l Total T < 12 nmol/l

16.33

49.66

Proportion of hypogonadism in 300 male patients with type 2 diabetes

(Mean age 58 years)

The role of testosterone in sexual function

International guidelines

• International guidelines emphasize the need for screening for hypogonadism in patients with ED

• The nitric oxide pathway, which is central to the physiology of erection, is testosterone dependent

• Testosterone therapy improves both erectile function and the response to PDE5 inhibitors in patients with ED and hypogonadism

• Testosterone therapy for ED and hypogonadism has recently evolved from monotherapy to combination therapy with PDE5 inhibitors

Morales et al., J Sexual Med 2004;1:69-81

Draw testosterone in all cases of male sexual dysfunction

Eugonadal testosterone levels

Normal libido Low libido

No hormonal treatment Check Prolactin

Low libidoNormal libido

Treat ED+/-testosterone

therapy

↑ Prolactin: Rx accordingly

Testosterone therapy

No success: Add Rx for ED

Unsuccessful: seek other causes

Hypogonadalhormonal screen

Management of patients with sexual dysfunction

Testosterone levels in sildenafil non-responders and responders at baseline (men with diabetes mellitus)

Kalinchenko S et al., Aging Male 2003;6(2):94-99

The role of androgens in erectile function

< 0.00118.6 ± 1.26.9 ± 1.3Total testosterone(nmol/l)

p-valueViagra

respondersn = 100

(Mean ± SD)

Sildenafil 100 mg

non-respondersn = 120

(Mean ± SD)

Prevalence of hypogonadism in 1027 diabetic and nondiabetic patients with erectile dysfunction

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

• Hypogonadism (T<12 nmol/l) is more prevalent in men with diabetes mellitus• The prevalence of hypogonadism increases over age;

men with diabetes mellitus are affected more frequently

22.3

34

All age groups

Normal fasting glucoseDiabetes mellitus

0

10

20

30

40

50

III IV V VI >VIIAge (Decades)

% H

ypog

onad

ism

Huebler D, Jockenhövel F et al., Int J Impot Res 2002;14 (Suppl. 4), Abstract P52 (2002)

Sexual parameters in 40 hypogonadal men treated with TE or testosterone undecanoate (TU, Nebido®)

** *

**

**

**

* * * **** ***

*

*** *

**

* ** **

****

*

**

*

*

*

**

**

** * *

***

*** *

0123456789

10

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

Tota

l ere

ctio

ns(n

umbe

rs)

00,5

11,5

22,5

33,5

44,5

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

Spon

tane

ous

mor

ning

erec

tions

(num

bers

)

00,5

11,5

22,5

33,5

4

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

Ejac

ulat

ions

(num

bers

)

T-enanthateT-undecanoate

* p < 0.05

Mean age: 41Range: 18 - 74 yrs

Week

Week

Most common associated risk factors in 521 men presenting with erectile dysfunction

39 3734

0

10

20

30

40

50

%

Hypertension Hypogonadism Multiple medications

Mean age: 59 years

Guay A et al., J Androl 2001;22(5):793-797

Shabsigh R et al., J Urol 2004;172:658-663

Testosterone therapy (5g Testogel®/d/12 wk) converts sildenafil 100 mg non-responders to responders in men with hypogonadism (total Testosterone <14 nmol/l) and erectile dysfunction

0

2

4

6

8

10

12

14

p=0.011IIEF* Total Score

Placebo + SildenafilTestogel + Sildenafil

Week 4 Week 8 Week 12 Endpoint

Mea

nch

ange

from

base

line

* International Index of Erectile Function

Treatment with testosterone

Basic principle of the clinical use of testosterone

1. To use natural testosterone2. To aim at physiologic serum T profiles


Goals of testosterone substitution

• Physiologic serum concentrations1

• Physiologic pharmacodynamics– Suppression of gonadotropins, leptin, SHBG

– Normal metabolism with normal levels for DHT and estradiol

– Normalisation and maintenance of bone and muscle mass

• Safe formulation

• No side effects

• Application should be convenient for the patient

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

Current formulations

50-100 mg dailyTestim®Testosterone gel

30 mg twice a dayStriant®Buccaltestosterone

BUCCAL

50-100 mg dailyTestogel®Testosterone gel

2.5-5 mg dailyAndroderm®Testosterone patch

TRANSDERMAL

120-240 mg dailyAndriol®Testosterone undecanoate

ORAL

1000 mg every 10-14 weeks

Nebido®T undecanoate

200-400 mg every 2-4 weeks

Testoviron®DepotTestosterone enanthate

200-400 mg every 2-4 weeks

Depo-testosterone cypionate®

Testosterone cypionate

INJECTABLE

DOSETRADE NAMEGENERIC NAME

Current formulations

Testo

stero

nebo

dypa

tches

Test

oste

rone

gel

Bucc

alta

blet

s

Long

-act

ing

test

oste

rone

inje

ctio

n

Test

oste

rone

tabl

ets/

caps

ules

Sho

rt-ac

ting

test

oste

rone

inje

ctio

n

Test

oste

rone

impl

ants

T sc

rota

lpat

ch

Nieschlag E et al., Hum Reprod Update 2004;10(5):409-19. Epub 2004 Aug 5

250 mg testosterone enanthate / 3 weeks i.m.

Test

ost e

r on e

(nm

o l/l)

Weeks

0

10

20

30

40

50

0 3 6 9 12

12 days

Poor pharmacokineticsBroad fluctuationsUnpleasant swingsof performance

i.m. injectionsSafe and in use for > 50 years

Intramuscular testosterone enanthate

Nieschlag E et al. 1976, Horm Res 7:138–45Jockenhövel F: Male hypogonadism. UNI_MED Verlag Bremen 2004

0

10

20

30

40

50

0 6 12 18 24

Hours

Serum T is outside of physiological range for

~25% of the time

Test

oste

rone

(nm

ol/l)

Oral testosterone undecanoate

Schürmeyer T et al. 1983, Acta Endocrinol 102:456-62Jockenhövel F: Male hypogonadism. UNI_MED Verlag Bremen 2004

Testosterone body patch (Andropatch®)

• First nonscrotal transdermal formulation

• Produces peak serum testosterone levels6–8 hours after application with a decline to low-normal or slightly subnormal levels by24 hours1,2

• The patches should be replaced daily

• After patch removal, testosterone levelsdecline rapidly to baseline2

1Meikle et al., J Clin Endocrinol Metab 1992;74(3):623-82Meikle et al., J Clin Endocrinol Metab 1996;81(5):1832-40

Testogel®

What is Testogel®?

• Testogel® is the first testosterone containing gel (5g, 1% T) for the treatment of male hypogonadism. Approx. 5 mg T (9-14%) are delivered to the blood stream.

• A single application per day (in the morning on clean, dry and intact skin on upper arm, shoulder and/or abdomen) restores physiological testosterone plasma levels.

• Testogel® offers great tolerability with only minimal skin irritability

• The potential problem of transfer of T to a partner can be prevented by clothing or reduced by showering after application– Note: showering or bathing is not recommended within the first

~ 6 hours after application

Time (hours)Patch 2.5 mg/day Gel 50 mg/day Gel 100 mg/day

0

10

20

30

40

0 8 16 24

Seru

m T

(nm

ol/l) Day 30

0

10

20

30

40

0 8 16 24

Day 90

Swerdloff R et al., J Clin Endocrinol Metab 2000;85(12):4500-4510

Effects of Testogel® on 24 h serum testosterone concentrations in 227 hypogonadal men

Seru

m T

(nm

ol/l)

010

2030

40

0 8 16 24

Day 1

Serum total and free T levels in hypogonadal men treated with Testogel®/AndroGel® for up to 36 months

T

Months0 6 12 18 24 30 36

T (n

mol

/l)

0

5

10

15

20

25

30

35

40

45 5 grams7.5 grams10 gramsnormal range

T

0 6 12 18 24 30 36

5 7.5 10

Free T

Months0 6 12 18 24 30 36

0.0

0.2

0.4

0.6

0 6 12 18 24 30 36

Free

T (n

mol

/l)

Wang C et al., J Clin Endocrinol Metab 2004;89(5):2085-2098

Months0 6 12 18 24 30 36

Seru

m D

HT

(nm

ol/l)

0

2

4

6

8

The maintenance of stable levels –metabolites of testosterone

DHT and estradiol plasma levels were elevated, following thecurve of testosterone


Months

Seru

m L

H (U

/l)

0 6 12 18 24 30 360

2

4

6

8

10

12

The maintenance of stable levels –gonadotropins

Gonadotropins are decreased with Testogel® therapy


Mean values of all dose groups

Change in total body lean and body fat mass in hypogonadal men after treatment with T-gel

Months0 6 12 18 24 30 36

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Months0 6 12 18 24 30 36

Tota

l bod

yfa

tcha

nge

(kg)

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Months

0 6 12 18 24 30 360

1

2

3

0 6 12 18 24 30 36

Cha

nge

tota

l bod

yle

an(k

g)

0

1

2

3

4


Months0 6 12 18 24 30 36

Cha

nge

leg

pres

s (k

g)

0

10

20


Change in muscle strength (leg press) in hypogonadal men after treatment with T-gel


Months0 6 12 18 24 30 36

Spi

neB

MD

cha

nge

(g/c

m2 )

0.00

0.01

0.02

0.03

0.04

0.05

0.06


Change in spine total BMD* levels in hypogonadal men after treatment with T-gel


*bone mineral density


Sexual parameters in hypogonadal men after treatment with T-gel

0 6 12 18 24 30 361

2

3

4

Months0 6 12 18 24 30 36

Sexu

al d

esire

(0-7

)

1

2

3

4

Months0 6 12 18 24 30 36

1.0

1.5

2.0

2.5

3.0

3.5

0 6 12 18 24 30 36Enjo

ymen

twith

part

ner(

0-7)

1.0

1.5

2.0

2.5

3.0

3.5

Months0 6 12 18 24 30 36

2

3

4

5

0 6 12 18 24 30 36

Erec

tion

satis

fact

ion

(0-7

)

2

3

4

5

Combination of testosterone and sildenafil –erectile function

*

*p = 0.029

0

1

2

3

4

5

Mea

nch

ange

from

base

line


Carry forward analysisIIEF: Erectile function domain

Placebo gel + sildenafilTestosterone gel + sildenafil

Shabsigh R et al., J Urol 2004;172:658–663

Shabsigh R et al., J Urol 2004;172:658–663

Combination of testosterone and sildenafil -orgasmic function

** **

*

0

0.5

1

1.5

2

Mea

nch

ange

from

base

line


**p < 0.01

*p < 0.10

IIEF: Orgasmic function domain

Placebo gel + sildenafil

Testogel / AndroGel®

+ sildenafil

Carry forward analysis

Greenstein A et al., J Urol 2005;173:530-532

Testosterone alone (Testogel® 5g daily, 3 months) significantly improves erectile function and sexual desire in 31 of 49 hypogonadal (< 400 ng/dl) patients with erectile dysfunction

before testosterone after testosterone

p < 0.001

0

5

10

15

20

25

30

IIEF-EF IIEF-SD

IIEF

Mai

n D

omai

n Sc

ore*

p<0.001

*The domain score represents the sum of the scores assigned to the individual questions in each domain. EF: erectile function; SD: sexual desire


Positive and negative mood score in hypogonadal men after treatment with T-gel

Months0 6 12 18 24 30 36

Posi

tive

moo

dsc

ore

4.25

4.50

4.75

5.00

5.25

5.50

0 6 12 18 24 30 364.25

4.50

4.75

5.00

5.25

5.50

Months0 6 12 18 24 30 36

1.00

1.25

1.50

1.75

2.00

0 6 12 18 24 30 36

Neg

ativ

e m

ood

scor

e

1.00

1.25

1.50

1.75

2.00


Months

0 6 12 18 24 30 36

PS

A (µ

g/l)

-1

0

1

2

3

4

5

6

Serum PSA level in hypogonadal men after treatment with T-gel



Long-term use of transdermal testosterone for the treatment of hypogonadal men

Prostate events• 5 (out of 163) subjects had elevated PSA (over 2.5

ng/ml at baseline)– 3 of these had had prostate cancer– All 3 were over 60 years of age– In the other 2, serum PSA returned to normal after

withdrawal of T-gel• No prostate ultrasounds were performed• 19 out of 163 (12%) subjects were found to have

enlarged prostates• Urine flow rate was less than 10 ml/sec in 26/163

subjects (16%)



Safety measurements with a total exposure of up to42 months:• Total cholesterol, LDL-C, HDL-C and triglycerides

showed no clinically relevant changes• Mean hemoglobin and hematocrit increased by 1.5

g/dl and 4.0 % respectively, after 12 months.• Mean serum PSA increased by 0.26 ng/ml

(p<0.001) at 6 months without progressive increases during the treatment period


Months

Hematocrit

0 6 12 18 24 30 36

Hem

atoc

rit(%

)38

40

42

44

46

48

50Hemoglobin

0 6 12 18 24 30 36

Hem

oglo

bin

(g/l)

130

140

150

160

170

Hematocrit and hemoglobin levels in hypogonadal men after treatment with T-gel



Other adverse events• Application site reactions occurred in 12 out of 163

subjects (7.4%)– 11 were mild and 1 moderate– 1 patient discontinued due to erythema and rash

• Gynecomastia occurred in 8 subjects (4.9%) during treatment

• Acne occurred in 12 subjects (7.4%)


Conclusion• Continuous application of transdermal testosterone

gel resulted in beneficial effects on sexual function and mood, body composition and bone

• Testogel® eases administration and does not cause skin irritation

• Testogel® is safe and effective for long-termtreatment of hypogonadal men

• Monitoring for prostate disease and hematocrit is advised to reduce adverse events with testosterone treatment

Nebido®

What is Nebido®?

• Composition • One ampoule of Nebido contains 1000 mg testosterone

undecanoate (TU) in 4 ml castor oil for intramuscular injection• Pharmacological properties• TU is an ester of the naturally occurring testosterone • Following administration of Nebido, TU is gradually released

from the depot and is cleaved by serum esterases intotestosterone and undecanoic acid

• An increase of serum testosterone concentrations abovebasal values can already be measured the very next day afterinjection

• Pharmacodynamic properties of TU are identical to thephysiological action of testosterone

O

CH3

CH3 O-C-(CH2)9-CH3

=

O

What is Nebido®?

Nebido®…• … is the first long-lasting injectable testosterone

preparation that leads to testosterone levels in the physiological range

• … avoids unphysiological peaks and troughs. This makes Nebido preferable to conventional injectables

• … usually has to be injected every 12 weeks in long-term treatment

• … is a safe, convenient and effective treatment

Behre HM et al., Eur J Endocrinol 1999;140:414–419

Single dose pharmacokinetics of Nebido®

Design: prospective, open label, non-randomised, phase I-study14 hypogonadal men received a single TU injection

Weeks after injection

Test

oste

rone

(nm

ol/l)

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8

refe

renc

era

nge

Nieschlag E et al., Clin Endocrinol 1999;51:757-763

Repeated injections of Nebido®

Prospective, open label, phase II study in 13 hypogonadal men receiving 4 injections of 1000 mg TU in castor oil at 6 week intervals

Weeks

Test

oste

rone

(nm

ol/l)

0

10

20

30

40

50

60

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

0

10

20

30

40

50

60

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

► Due to T accumulation, an injection interval of 6 weeks is too frequent.

refe

renc

era

nge

Eckardstein S et al., J Androl 2002;23:419–425

Extension of Nebido® injection intervals to 12 weeksin 7 hypogonadal men

Weeks

Test

oste

rone

(nm

ol/l)

6 week 12 week intervals7-11 week

0

10

20

30

40

50

60

0 12 24 36 48 60 72 84 96 108 120 132 144

refe

renc

era

nge

Testosterone after a single injection of Nebido® in 14 hypogonadal men and after the 13th injection after continued treatment for 102 weeks

Eckardstein S et al., J Androl 2002;23:419–425

1st injection – week 0 13th injection – week 102

Weeks post administration

Test

oste

rone

(nm

ol/l)

107 108 109 110 111 112 113 114

13th injection

102 103 104 105 1060

10

20

30

40

0 1 2 3 4 5 6

1st injection

0

10

20

30

40

0 1 2 3 4 5 6

refe

renc

era

nge

Comparison of the kinetics of standard TE to thenew, long-acting TU (Nebido®)

Months

Testosterone levels (nmol/l)

1000 mg TU i.m. ( ) 250 mg TE ( )

0

10

20

30

40

0 6 12 18 24 30

refe

renc

era

nge

Schubert M, Jockenhövel F et al. 2004, J Clin Endocrinol Metab 89:5429-34

Recommended treatment regimen of Nebido®

Application• Inject deep intramuscularly (m. gluteus)• Inject slowly (take 1 minute)

Control: T for therapyindividualisation

HbPSA

Control: HemoglobinPSADRE

0 6 18 30WEEKS

Individualisation of injection intervalswith Nebido®

• Measurement of T levels before 4th injection at week 30

Remember: The 1st interval should be reduced to 6 weeks

Aim: Serum trough testosterone levels should be in the lower third of the normal range (12-18 nmol/l) but the clinical symptomatology for individualisation of therapy should also be considered

S= Screening, * p < 0.05

T-Enanthate T-Undecanoate

* * *****

**

******

0

10

20

30

40

50

60

70

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

Sexu

al th

ough

t/fan

tasy

(sco

res)

* * * **

Week

* * * * * * *** *

** ******

0

10

20

30

40

50

60

70

S 0 3 6 9 1215 18 21 24 27 30

Sexu

al in

tere

st/d

esire

(sco

res)

**

**

** **

** *

*

*

*

* *

** ***

*

0

10

20

30

40

50

60

70

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

tisfa

ctio

nw

ithse

xlif

e (s

core

s)

Response to therapy with TE and long-actingTU (Nebido®): Sexual parameters

Hübler D, Jockenhövel F et al. 2002, Int J Impot Res 14, Suppl 4, S51

Week

Week

Response to therapy with TE and long-actingTU (Nebido®): Sexual parameters

S= Screening, * p < 0.05



* *

*

**

* * *

**

**

**

00,5

11,5

22,5

33,5

4

S 0 6 12 18 24 30

**

* * **

Ejac

ulat

ions

(num

bers

)

***

* * **

**

** *

**

** ***

*

00,5

11,5

22,5

33,5

44,5

S 0 6 12 18 24 30

Wak

ing

erec

tions

(num

bers

)

**

* ** *

*** *

**

***

*

0123456789

10

S 0 6 12 18 24 30

Tota

l ere

ctio

ns(n

umbe

rs)

Week

Week

Week

0

10

20

30

40

50

60

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

* ** *

**

** *

Dep

ress

ion

(sco

res)

01020304050607080

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

** * * *

** * * **

Fatig

ue(s

core

s)

05

1015202530354045

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

Agg

resi

vity

(sco

res)

05

101520253035404550

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

*

Anx

iety

(sco

res)

Week

Response to therapy with TE and long-actingTU (Nebido®): Psychological parameters


0% 13% 54%

0%

20%

40%

60%

80%

100%

Baselinen = 0/22

Responders after6 weeks, n = 3/22

Responders after24 weeks, n = 12/22

Patients with normal erectile function in % at baseline, after 6 and 24 weeks of Nebido® therapy

IIEF changes/development under Nebido® i.m. in responders

(EF = erectile function; SD = sexual desire)

12

4.5

25

8.40

10

20

30

EF SD

Baseline (22 pat.) Week 24 (12 pat.)


Hem

atoc

rit(%

)

Week

42

44

46

48

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

Erythropoiesis with TE / TU (Nebido®) treatment in 40 hypogonadal men

Mean age: 41; range: 18 - 74 years

Week

14

15

16

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

Hem

oglo

bin

(g/d

l)

Huebler D, Jockenhövel F et al. 2000, Endo Abstract Book:567

0

0,5

1

1,5

Effect of long-term testosterone treatment (i.m. TU in intervals of 12 weeks) on prostate specific antigen (PSA)in 40 hypogonadal men

Mean age: 41; range: 18 - 74 years

PSA

(ng

/ml)

baseline 30 weeks 54 weeks 90 weeks 114 weeks 138 weeks

Sommer F, Jockenhövel F et al. 2005, J Sex Med 2 (Suppl. 1):50-51

Conclusion

• Androgen therapy with intramuscular TU (Nebido®) maintains serum testosterone levels within the physiological range

• Unphysiological peaks and troughs are largely avoided • Intervals of 10-14 weeks were found to be adequate

with the necessity for individualisation of therapy according to clinical symptoms + trough testosterone level

• Patients feel emotionally stabilised and fluctuations in sexual function and mood are prevented

• Therapy with long-acting intramuscular TU has been shown to be well tolerated, a result that is confirmed by treatment experience of up to 7.5 years

Overall conclusion

• Long-term use of transdermal testosterone and intramuscular testosterone undecanoate are effective and safe treatment options for hypogonadism

• Long-term treatment with TU leads to physiological serum T levels

• Monitoring of T levels, for prostate disease and hematological parameters should be performed throughout the time of treatment

Thank you very much for yourattention

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