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8NEBI68
Hypogonadism and Testosterone Replacement
Jamie Smith
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Testosterone and its metabolites
Sexual differentiationMusculatureBone massErythropoiesisPsychotropic actionPotency/libidoLipid metabolism
Bone massEpiphyseal closurePsychotropic actionLipid metabolismFeedback actionProstate
Sexual differentiationSecondary hairSebum productionProstate
TestosteroneTestosterone
DihydrotestosteronDihydrotestosteronee
OestradiolOestradiol
Aromatas
Aromatasee5Ω -
5Ω -
Reductase
Reductas
e
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Binding of testosterone (T)
T firmly T firmly bound to bound to
SHBGSHBG60%60%
BIOAVAILABLE TESTOSTERONE BIOAVAILABLE TESTOSTERONE = = Albumin-bound TAlbumin-bound T + + Free TFree T
Free TFree TT loosely bound T loosely bound to albuminto albumin
2%2%38%38%
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Clinical picture of testosterone deficiency1
• 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 well-beingReduced well-being• 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
1. Nieschlag E and Behre HM. Testosterone: action, deficiency, substitution (3rd Edition). Cambridge University Press; 2004.
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Sex hormones and hypogonadism
1. Jöckenhovel F. Male Hypogonadism. UNI-MED, Bremen; 2004.
LHLHFSHFSH
GnRHGnRH
HypothalamuHypothalamuss
PituitaryPituitary
TestisTestis
SECONDARY SECONDARY HYPOGONADISMHYPOGONADISMSecondary testicular failure Secondary testicular failure
Hypogonadotrophic Hypogonadotrophic hypogonadismhypogonadism
PRIMARY HYPOGONADISMPrimary testicular failure
Hypergonadotrophic hypogonadism
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Causes of primary hypogonadism1
• Congenital
– Chromosomal defects e.g. Klinefelter's syndrome
– Congenital anorchia
– Androgen receptor/enzyme defects
• Acquired
– Testicular trauma/torsion
– Surgical removal
– Chemotherapy/irradiation
• Complications of illness
– e.g. diabetes, renal failure, alcoholic liver disease, cirrhosis
1. Nieschlag E et al. Human Reprod Update 2004;10(5):409-419.
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Causes of secondary hypogonadism1,2
• Congenital
– Kallmann’s syndrome
– Idiopathic hypogonadotrophic hypogonadism (IHH)
– Prader-Willi syndrome
• Acquired
– Prolactinoma
– Pituitary adenoma
– Hypothalamic tumour
– Anabolic steroid abuse
• Complications of illness
– e.g. AIDS, haemochromatosis
1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002.2. Nieschlag E et al. Human Reproduct Update 2004;10(5):409-419.
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Late-onset hypogonadism
• A clinical and biochemical syndrome associated with advancing age and characterised by typical symptoms and a deficiency in serum testosterone levels1,2
1. Nieschlag E et al. Eur Urology 2005;48:1-4.2. Vermeulen A et al. J Clin Endocrinol Metab 1996;81:1821-1826.
SHBG SHBG Free T (x100) Free T (x100) TestosteroneTestosteroneSHBG SHBG Free T (x100) Free T (x100) TestosteroneTestosterone
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
leve
l (n
mo
l/L
)
Age
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Hypogonadism incidence and age (US data)
0
5
10
15
20
25
Overall 48-59 60-69 70-79
Inci
dence
per
1,0
00 p
ers
on-y
ears
Age (years)• Expected 481,000 new cases p.a. in US men 40-69 yrs
1. Araujo A et al. J Clin Endocrinol Metab 2004;89(12):5920-5926.
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Hypogonadism and CV risk factors
• Low testosterone levels in men frequently co-exist with
– Type 2 diabetes mellitus
– Erectile dysfunction
– Abdominal obesity
– Other CV risk factors
• Component of the metabolic syndrome?
CV, cardiovascular
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Prevalence of hypogonadism in diabetes
0
10
20
30
40
50
Free T Total T Bioavailable T
Perc
enta
ge o
f pati
en
ts
1. Dhindsa S et al. J Clin Endocrinol Metab 2004; 89(11): 5462-5468.
• n=103 men with type 2 diabetes
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Hypogonadism in diabetic vs nondiabetic men with ED1
22.3
34.0
All ages
ED no diabetes Diabetes
0
10
20
30
40
50
30-39 40-49 50-59 60-69 >70Age (Years)
% H
ypog
onad
ism
(T <
12nm
ol/L
) p <0.0001p <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
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Diagnosing hypogonadism
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GP (Pre-referral): ASSESSMENT
General HistoryGeneral History
Drug HistoryDrug History
Physical Physical examinationexamination
Past Medical Past Medical HistoryHistory
Symptom duration and social history
Previous testicular or head injury? Chronic illness?
General exam + BMI, testicular size, secondary sexual hair
Prescription drugs? Drug abuse?
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When should you measure testosterone?1
Circadian rhythm of testosterone
1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002.
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Patient history and physical examinationPatient history and physical examination
Measure serum testosterone levels between 7-11amMeasure serum testosterone levels between 7-11am
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 levelMeasure 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 8-12nmol/L T 8-12nmol/L normal normal
Prolactin and Prolactin and FSH/LHFSH/LH
T 8-12nmol/L, T 8-12nmol/L, and and Prolactin Prolactin
or abnormal or abnormal FSH/LHFSH/LH
T <8nmol/LT <8nmol/L
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Patients with borderline testosterone levels (8-12 nmol/l)1,2
• Consider additional biochemical tests
– Gonadotrophins, SHBG, prolactin
• Careful consideration of comorbidities
• Calculate free testosterone (see online calculator at www.issam.ch/freetesto.htm)
• Counsel patient regarding treatment options
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.
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Who should receive testosterone treatment? • Men with clinical symptoms and testosterone <8
nmol/l1
• Men with clinical symptoms and testosterone 8-12 nmol/l where additional investigations indicate presence of hypogonadism1
• Older men with significant symptoms
– Long-term risks /benefits have yet to be clearly demonstrated
1. Nieschlag E et al. Int J Androl 2005;28:125-127
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Who should receive 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
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Treating hypogonadism
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Goals of testosterone replacement therapy1,2
• Restore physiological testosterone levels
• Alleviate symptoms of androgen deficiency
• Induce or restore physiological functions
• Prevent long-term health risks of androgen deficiency
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.
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0
1
2
3
4
5
Week 4 Week 8 Week 12 Endpoint
Placebo +Sildenafil100mgTestosterone+ Sildenafil100mg
1. Shabsigh R et al. J Urol 2004; 172: 658-663
p=0.029
Testosterone converts sildenafil non-responders to responders in men with hypogonadism and erectile dysfunction1
p=ns
p=nsp=ns
Mean c
hang
e f
rom
base
line
IIE
F ere
ctile
funct
ion
dom
ain
n=75 hypogonadal men with ED
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Treatment options
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19401940 Testosterone implantTestosterone implant
19541954 Short-acting injectable Short-acting injectable testosteronetestosterone
19771977 Oral testosteroneOral testosterone
19921992 Testosterone patchTestosterone patch
19951995 Testosterone patchTestosterone patch
19981998 Testosterone patchTestosterone patch
20022002 Testosterone gelTestosterone gel
20042004 Buccal testosterone tabletBuccal testosterone tablet
20042004 Long-acting injectable Long-acting injectable testosteronetestosterone
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Oral testosterone (Restandol®;Andriol®/TestocapsTM)1,2
• Tablets containing 40mg testosterone undecanoate as a maintenance dose taken 2-3 times a day
• Route of absorption is via lymphatic system
– Therefore needs to taken with a meal containing dietary fat
– Without dietary fat absorption is minimal, and pharmacokinetics unreliable
1. Nieschlag E et al. Human Reproduct Update 2004; 10 (5):409-419.2. Organon Laboratories Limited. Restandol® SPC; May 1998.
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Buccal testosterone1,2
(Striant®)• 30mg testosterone tablet placed above incisor
tooth twice daily
• Avoids hepatic inactivation
– Absorbed across oral mucosa
• Good pharmacokinetics, achieving normal testosterone levels
• May be application difficulties
• Risk of site reactions
1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.2. Ardana Bioscience. Striant® SPC; March 2005.
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Subdermal(Testosterone implants)• Testosterone pellets (100-600mg) implanted
subdermally2
– Three to six pellets (600mg to 1.2g) usually maintain plasma testosterone concentrations for 4-6 months1
• Risk of supraphysiological testosterone levels
• Minor surgical procedure
– Can be painful/infection risk/scarring
– 8.5% extrusion of pellets3
– Previous implants are not removed
– A new insertion site is used each time
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.
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Transdermal patches1,2
(e.g. Andropatch®)
• 2.5-7.5mg testosterone delivered, starting dose
• Daily circadian profile of testosterone delivery3,4
• Alcohol base to enhance permeation
• Skin reactions common (>50% patients)3,4
• Size of patch can be obtrusive
• May make crinkling noise
1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.2. 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.
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Transdermal gels1-5
(Testogel®, Tostran®, Testim®)• 50-100 mg testosterone gel applied each
morning to shoulders, back, or abdomen*
• Daily circadian profile of testosterone delivery2,4
• Skin reactions in 4-10% patients2,3*
• Avoid washing for 6 hours*
• Risk of transfer to another person via skin contact
• Daily patient compliance required
*Details may vary; refer to product information1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.2. 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):2839-2653.5. ProStrakan Ltd. Tostran ® SPC; April 2007.
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Intramuscular injections - short acting1,2
(Sustanon® 100; Sustanon® 250; Testoviron®)• Currently the most widely used form of testosterone
• Two short-acting preparations widely available in UK
– Sustanon 100 (testosterone: propionate/phenylpropionate/ isocaproate in arachis oil)
– Sustanon 250 (testosterone: propionate/phenylpropionate/ isocaproate/decanoate in arachis oil)
• Injection every 2 weeks (Sustanon 100) or 3 weeks (Sustanon 250)2,3
• Peak and trough testosterone levels
• Injection site reactions/patient discomfort
• Reaction to excipients (nut allergy)
1 Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.2. Organon Laboratories Limited. Sustanon® 100 SPC; February 20043. Organon Laboratories Limited. Sustanon® 250 SPC; January 2006.
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Pharmacokinetics of UK available injectable testosterone preparations: Sustanon 2501
1. Lane HA et al. Endocrine Abstracts 2006;11:P677.
0
10
20
30
40
1 2 3 4
Sustanon 250
Weeks
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Intramuscular injections - long acting1
(Nebido®)• 1000 mg testosterone undecanoate in 4 ml castor
oil
• Loading dose at 6 weeks, and then every 10 to 14 weeks1
• Testosterone levels maintained within the physiological range2
– Avoids frequent peaks and troughs in testosterone levels that may be seen with short-acting injections3
• Increased patient convenience (quarterly injections)
• Injection site reactions/patient discomfort
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.
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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 injectable testosterone preparations: Nebido1-3
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
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Monitoring patients on testosterone therapy
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Parameters to monitor or to be aware of during therapy1,2
• Prostate
• Haematocrit and haemoglobin
– Increased levels particularly associated with supraphysiological levels of testosterone
• Blood lipids
• Liver function
• Miscellaneous adverse effects of testosterone
– E.g. gynaecomastia, acne, oily skin, priapism, sleep apnoea
• Clinical response to therapy
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.
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Endocrine Society: recommendations1
ParameterParameter BaselineBaseline 3 month3 month AnnualAnnual
PSA Y Y Y
DRE Y Y Y
Haematocrit Y Y Y
Testosterone - Y Y
BMD Y - Y
1. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.
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Endocrine Society: Prostate monitoring1
• Urological consultation should be sought if there is:
– Verified PSA >4.0 ng/ml
– Increase in PSA concentration >1.4ng/ml within any 12-month period of testosterone treatment
– PSA velocity >0.4ng/ml/year
– Detection of a prostatic abnormality on DRE
1. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.
