The Testosterone Debate by Dr Robert McLachlan

Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
The General Practice Education Day
Disclosures
Healthed / Generation Next
August 22nd Sydney
None
Update on Androgen Deficiency
Acknowledgments
Robert I. McLachlan, FRACP, PhD
Director, Andrology Australia
Principal Research Fellow, Hudson Institute of
Medical Research
Consultant Andrologist, Monash IVF Group
David Handelsman: ANZAC Institute, Sydney
Gary Wittert:
T4DM study Univ Adelaide
Carolyn Allan: Hudson Institute, Melbourne
Endocrine Society Australia Working Party
Recent concepts and interventions
•
Sex hormone actions
•
‘At risk’ groups – challenges in detection
•
Controversies in management
•
Treatment options & monitoring
Androgen Deficiency (AD)
No unequivocal clinical features nor agreed serum
biomarkers of androgen sufficiency
• Diagnosis requires synthesis of clinical features
and biochemistry
• Androgen deficiency is a syndromic diagnosis not
one defined by blood levels:
– Statistical population-based distribution
(e.g. serum calcium)
– Therapeutic targets
(e.g. cholesterol)
Bhasin S et al. Steroids. 2008;73:1311.
Androgen deficiency in adults
Androgen deficiency in adults
General
General
Sexual
Sexual
Organ specific features
Organ specific features
–  sense of well being, poor concentration
– tiredness, poor stamina
– mood change - depression, irritability
–  libido
–  ejaculate volume
– erectile failure
–
–
–
–
 muscle mass and strength
osteoporosis and fracture
increased fat mass
cardiovascular & metabolic
–  sense of well being, poor concentration
– tiredness, poor stamina
– mood change - depression, irritability
–  libido
–  ejaculate volume
– erectile failure
–
–
–
–
Symptoms screening tools
like AMS not helpful
 muscle mass and strength
osteoporosis and fracture
increased fat mass
cardiovascular & metabolic
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Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Androgen deficiency in adults
General
(prostate, skin)
5a-reductase
(5-10%)
Testosterone
What mediates these
diverse actions?
6 mg/day
aromatase
(0.2%)
Hepatic oxidation &
conjugation
Renal excretion
Organ specific features
–
–
–
–
 muscle mass and strength
osteoporosis and fracture
increased fat mass
cardiovascular & metabolic
Inactivation
pathway
Androgen receptor
DHT
Direct pathway
(muscle)
Androgen receptor
Estradiol
Y
–  libido
–  ejaculate volume
– erectile failure
Amplification pathway
LH
–  sense of well being, poor concentration
– tiredness, poor stamina
– mood change - depression, irritability
Sexual
Testosterone: Three hormones in one
GnRH
Estrogen receptors
Diversification pathway
(brain, bone)
D Handelsman www.ENDOTEXT.org
Implications of ‘Three hormones in one’
J Clin Endo Metab 2010, 95, 2536
Testosterone is the molecule of choice for
physiological androgen replacement
Testosterone Therapy in Men with Androgen Deficiency
Syndromes: Endocrine Society Clinical Practice Guideline
Use, misuse and abuse of androgens. The Endocrine
Society of Australia consensus guidelines for androgen
prescribing
Med J Australia 2000 ;172:220
Published Online: July 02, 2013
Conway A, Handelsman DJ, Lording DW, Stuckey B, Zajac JD
.
Update in preparation .......
Androgen replacement is warranted
at ANY age when deficiency due to
Hypothalamo-pituitary-testicular axis
Hypothalamus
Defined testicular or hypothalamo-pituitary
disease
GnRH
Testosterone
Estradiol
Benefit of physiological replacement is based
on evidence of safety & efficacy
Pituitary
Inhibin B
LH, FSH
pulsatile
Behaviour
Challenge: to identify the patients
Secondary testicular
failure
Prostate
Muscles
Skin
& Hair
Lipids
Bone
marrow
Testis
Primary testicular
failure
2
Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Basic approach to androgen deficiency
Think of it: history and examination
Confirmatory blood testing
Repeat total T
 30% normalize on repeat
1st Blood: Serum total testosterone (fasting)
Serum LH: primary vs secondary testicular failure
between 0800 and 1000hr : circadian variation
Adjust time frame for shift workers
Wittert G. Curr Opin Endocrinol Diabetes Obes. 2014 ;21 239.
When a pathological cause of AD suspected
Low T, low LH ? Pituitary failure
•
•
•
•
Serum prolactin (prolactinoma)
Iron studies
(haemochromatosis)
Pituitary function : cortisol, FT4, TSH, growth hormone
Hypothalamo-pituitary MRI
Low T, high LH Primary testicular failure
•
•
Karyotype
suspected Klinefelters Syndrome
Y chromosome microdeletion
in infertility context
Serum SHBG and calculated free T
 Elevation: age, hyperthyroidism, liver
disease, anti-epileptic therapies
 Suppression: obesity, insulin resistance,
androgen exposure
Classic Androgen deficiency
Primary (high LH)
impaired testis function
Klinefelter’s syndrome
Infertile men
Testicular damage vascular, cancer Rx
Secondary (low LH) hypothalamo-pituitary
Prolactinoma
Congenital GnRH deficiency (rare)
Klinefelter’s Syndrome – 47XXY
Classical KS
in textbooks
Commonest chromosomal disorder
gynecomastia
Profound learning
difficulties
narrow shoulders
1:600 males
reduced body hair
Commonest cause of undiagnosed androgen deficiency
Almost all androgen deficient as adults
- Benefit from replacement
70% escape diagnosis lifelong
Bojesen JCEM 2003
detection strategies a major challenge
Reject your stereotypical images of KS
abdominal obesity
small testicular
volume
varicose veins
horizontal pubic
hairline
From: Nieschlag and
Behre, 2007
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Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Classical KS
in textbooks
gynecomastia
Profound learning
difficulties
narrow shoulders
Not always!!
may appear entirely normalreduced
and
body hair
adequately virilised when clothed
abdominal obesity
small testicular
volume
varicose veins
horizontal pubic
hairline
Classical KS
in textbooks
narrow shoulders
Not always!!
may appear entirely normalreduced
and body hair
adequately virilised when clothed
gynecomastia
abdominal obesity
horizontal pubic
hairline
~10,000 missed KS males in Australia
small testicular
volume
Failure to systemically examine male
genitalia : flaw in education & practice
From: Nieschlag and
Behre, 2007
varicose veins
From: Nieschlag and
Behre, 2007
Small testes found on routine
genital examination
Classical KS
in textbooks
narrow shoulders
Not always!!
may appear entirely normalreduced
and body hair
adequately virilised when clothed
gynecomastia
abdominal obesity
horizontal pubic
hairline
small testicular~10,000 missed KS males in Australia
volume
Failure to systemically examine male
genitalia : flaw in education & practice
From: Nieschlag and
varicose veins
Behre, 2007
Klinefelter’s
syndrome: The most overlooked
cause of
androgen deficiency. St John B & McLachlan RI
Endocrinology Today 2015; 4(1): 8-14
Small testes found on routine
genital examination
All types of practice
Male health evaluation
requires full history &
routine physical exam
Male infertility : IVF programs
Male factor infertility accounts for ~30%
Spermatogenic failure is most common cause
Azoospermia : ~14% are Klinefelters
Androgen deficiency ~ 1 in 8 infertile men
4
Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Male infertility : IVF programs
Now it gets tricky.....
Male factor infertility accounts for ~30%
Low testosterone associated with
Spermatogenic failure is most common cause
• Chronic disease
• Obesity
• Diabetes
• ? Age per se
Azoospermia : ~14% are Klinefelters
Androgen deficiency ~ 1 in 8 infertile men
When if ever is testosterone treatment warranted?
Now it gets tricky.....
1936 University of Washington Olympic Gold Medal Crew
Low testosterone associated with
• Chronic disease
• Obesity
• Diabetes
• ? Age per se
All share common
non specific
symptoms with
androgen deficiency
When if ever is testosterone treatment warranted?
Courtesy J Amory
1936 University of Washington Olympic Gold Medal Crew
50-Year Reunion
Courtesy J Amory
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Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Healthy Man Study
Low “T” - How to Sell Disease
Sartorius G et al Clin Endocrinol 2012 ;77:755
Schwartz & Woloshin JAMA June 3rd 2013
40
‘A man on TV is selling me a miracle cure that will
keep me young forever. It’s called Androgel for
treating something called ‘Low T’, a
pharmaceutical company–recognized condition
35
affecting millions of men with low testosterone,
Serum Testosterone (nmol/L)
Testosterone
35
30
25
20
15
10
5
previously known as getting older.’
n=325 men, 2900 serum specimens
0
40
50
—The Colbert Report,1st December 2012
70
80
90
Age (years)
Healthy Man Study
2

1

Andropause
hypothesis
Sartorius G et al Clin Endocrinol 2012 ;77:755
40
Testosterone
Serum Testosterone (nmol/L)
60
Barometer of
Health
hypothesis
Age
35
1

Serum T did not vary with age
2

30
25
1

T
20
Disease
2

15
1

10
2

5
Symptoms
n=325 men, 2900 serum specimens
0
40
50
60
70
80
90
Age (years)
European Male Aging Study (EMAS) Relationship
between Age and Testosterone in 3220 Men
>60%
population
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
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Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
European Male Aging Study (EMAS) Relationship
between Age and Testosterone in 3220 Men
Age
1

BMI <25
2

Barometer of
Health hypothesis
1

Andropause
hypothesis
2

T
2

BMI 25-29
Disease
2 A
BMI ≥30
22 B
Symptoms
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
2

Barometer of
Health hypothesis
1

Andropause
hypothesis
Age
1

Philosophy of Testosterone Treatment
Physiological replacement (‘natural therapy’)
2

Replicate normality in HYPOGONADAL men
T
2

Disease
Definition and identification of subjects
2 A
? Testosterone
as adjunct in
management
----------------------------------------------------------------------------
22 B
Symptoms
Pharmacological treatment (as a drug)
Dose for desired effect in EUGONADAL men
Risk : benefit ratio
What is your goal?
Does testosterone
work?
Are there better
approaches?
When is enough
too much?
Serum T 6.4 nM: maybe testosterone will help?
7
Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Serum testosterone rises as body weight falls
Grossmann M JCEM 2011, 96, 2341
Serum T
levels
Weight loss
20
Testosterone for Prevention of
Type 2 Diabetes in High Risk Men:
placebo-controlled RCT
Metabolic syndrome & diabetes
2.
Frailty – age or disease related sarcopenia
3.
Depression
4.
Cardiovascular health
Secondary endpoints:
• body composition
• systemic & vascular inflammation
• mood, QOL, psychosocial function
• adherence to the lifestyle program
Age
1

2

T
2

Disease
2 A
~420 randomised
Target 1000
2

Barometer of
Health hypothesis
1

Age
1

2

Barometer of
Health hypothesis
1

Andropause
hypothesis
http://www.t4dm.org.au/
Hypothesis:
Reduce onset/reverse Type 2 DM in men with low T,
over and above a lifestyle program
Andropause
hypothesis
1.
40
Ageing, overweight men with type 2 diabetes and low T levels
→ lifestyle measures such as weight loss and exercise
Wittert G
Testosterone as a drug – emerging
therapeutic roles requiring RCT data
2

? Testosterone
as adjunct in
management
22 B
Symptoms
Current climate in TRT in aging men
Testosterone Replacement Therapy Faces FDA Scrutiny
Garnick M. JAMA , 2015: 313, 563
T
2

Disease
2 A
Compelling case
for RCTs on
specific endpoints
• efficacy
• safety
22 B
Disease Mongering of Age-Associated Declines in
Testosterone and Growth Hormone Levels
Perls T & Handelsman DJ
J American Geriatrics Society, 2015 in press
Symptoms
PBS support threshold in men > 40 yr without a
defined testicular or pituitary cause lowered to 6nM
8
Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Cardiovascular risk : evidence is
contradictory and inconclusive
Observational studies
In older men: increased and decreased CV events
Mostly retrospective studies, non-randomised,
multiple biases and confounders
US FDA review : no increase of major CV
events in testosterone-treated men.
But FDA mandates labelling of US testosterone
products to warn about a possible increased risk of
heart attack and stroke
-----------------------
• Use with caution, if at all, in older men, especially
RCTs
↑ CV events with high dose Te therapy in frail old men
Unconfirmed in another RCT in similar men
with known cardiovascular disease.
• Unstable cardiac disease or recent CV (within 6-12
months) constitute contraindications
Meta-analysis: 3,000 mainly older men - ↑ in range
of CV events ..many limitations to data
Dr ‘No Testosterone’?
Dr ‘Not first option and not
without deep reflection’
:
Managing Homer
• Lifestyle
– Diet
– Exercise
• Medical
Testosterone does not enhance efficacy of
sildenafil in erectile dysfunction: RCT data
• 40-70 years
• Total T <10 nM
• Optimal sildenafil dose
• Testosterone / placebo gel for 14 weeks
– diabetes, hypertension, dyslipidemia
• Psychosexual issues
– Judicious use of PDE5 inhibitors
Testosterone no added benefit to sildenafil alone
• Consideration of androgen therapy
– Realistic benefits – RCT data low quality
– Risks - ? cardiovascular
Spitzer M Ann Intern Med 2012 57:681
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Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Testosterone replacement:
individualized approach
Testosterone
preparations
Testosterone
preparations
2002
1940
Tailored to clinical setting
induction virilisation vs replacement in adulthood
1992
1954
Compliance
2004
1995
Age
2004
1977
2004
1998
Reandron
Courtesy of M Zitzmann, Munster
Testosterone Preparations
T gel, patch,
axilla,cream
Adoption of Reandron Australia 2006-2010
T esters im
30
Serum
20
Te
(nM)
T implant
10
T undecanoate im
‘Reandron’
0
1
2
0
2
Days
4
6
8
10
Weeks
No oral or synthetic formulations
Normal range
Handelsman MJA 2012:196, 642
↑
2↑↑012
Issues with T undecanoate
15 years experience Europe, 10 yr in Australia
Monitoring androgen therapy
‘Age-appropriate’ general medical care
lipids, blood pressure, weight
Widey reported in long term use
Zitzmann M J Sex Med 2013: 10:579
Wang C
J Androl 2010;31:457
Inject 4ml slowly – 2 mins !
Special considerations:
elderly: avoid long acting formulations - polycythemia
prostate health
cardiovascular health
sleep apnea – prior history or risk factors
Post injection cough
~1:50 injection; mild/mod.
Desire for fertility is a contraindication
Midddleton Eur J Endocrinol 2015 Jan 30
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Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Systematic reviews of prostate cancer risk
Testosterone therapy in hypogonadal men and
prostate cancer risk: a systematic review.
Shabsigh R Int J Impot Res 2009;21:9
44 studies: No increased prostate cancer risk
Key messages
1. Native testosterone is preferred sex steroid
2. Focus on identifying established deficiency
3. Low T level are frequently associated with common
comorbidities - these ought be the primary focus
Effect of testosterone replacement therapy on
prostate cancer: systematic review & meta-analysis.
4. RCT data on testosterone as a ‘drug’ awaited
Cui Y Prostate Cancer Prostatic Dis 2014;17:132
5. Testosterone therapy is readily monitored:
22 RCTs, n= 2351: no increase in short-term
convenience = compliance
Long-term data are warranted
www.andrologyaustralia.org
Clinical summary guides
Courses for GPs
accredited education provider through RACGP
Course description
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Klinefelters, PE, prostatitis
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androgen deficiency, erectile
Aboriginal and
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disease, prostate disease.
Tailored knowledge and skills to
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Men’s sexual and
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reproductive health General Practice, Monash Univ.
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Curatio PowerPoint TemplateControversies in Male Hypogonadism
Bradley D. Anawalt, MD
Many thanks!
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