Acknowledgments Robert I. McLachlan, FRACP, PhD · Curatio PowerPoint TemplateControversies in Male...

Curatio PowerPoint TemplateControversies in Male Hypogonadism

Bradley D. Anawalt, MD

1

The General Practice Education DayHealthed / Generation Next

August 22nd Sydney

Update on Androgen Deficiency

Robert I. McLachlan, FRACP, PhD

Director, Andrology Australia

Principal Research Fellow, Hudson Institute of Medical Research

Consultant Andrologist, Monash IVF Group

Disclosures

None

David Handelsman: ANZAC Institute, Sydney

Gary Wittert: T4DM study Univ Adelaide

Carolyn Allan: Hudson Institute, Melbourne

Endocrine Society Australia Working Party

Acknowledgments

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

General– sense of well being, poor concentration– tiredness, poor stamina – mood change - depression, irritability

Sexual– libido – ejaculate volume– erectile failure

Organ specific features– muscle mass and strength– osteoporosis and fracture– increased fat mass– cardiovascular & metabolic





Symptoms screening tools

like AMS not helpful



2





What mediates these

diverse actions?

Direct pathway

(muscle)

Estradiol

Diversification pathway (brain, bone)

D Handelsman www.ENDOTEXT.org

aromatase

(0.2%)

Androgen receptor

Estrogen receptors

DHT

GnRH

LH Amplification pathway (prostate, skin)

Inactivation pathway

5a-reductase

(5-10%)

Hepatic oxidation &

conjugation

Renal excretion

Androgen receptorY

Testosterone6 mg/day

Testosterone: Three hormones in one

Testosterone is the molecule of choice for

physiological androgen replacement

Implications of ‘Three hormones in one’

Testosterone Therapy in Men with Androgen Deficiency Syndromes: Endocrine Society Clinical Practice Guideline

Published Online: July 02, 2013

J Clin Endo Metab 2010, 95, 2536

Use, misuse and abuse of androgens. The Endocrine Society of Australia consensus guidelines for androgen prescribing Med J Australia 2000 ;172:220

Conway A, Handelsman DJ, Lording DW, Stuckey B, Zajac JD

.

Update in preparation .......

Androgen replacement is warranted at ANY age when deficiency due to

Defined testicular or hypothalamo-pituitary disease

Benefit of physiological replacement is based on evidence of safety & efficacy

Challenge: to identify the patients

Hypothalamo-pituitary-testicular axis

GnRH

Inhibin B

Pituitary

LH, FSH

pulsatile

Testosterone

Estradiol

Hypothalamus

Testis

Behaviour

Prostate

Muscles

Skin & Hair

Lipids

Bone marrowPrimary testicular

failure

Secondary testicular

failure



3

Basic approach to androgen deficiency

Think of it: history and examination

1st Blood: Serum total testosterone (fasting)

between 0800 and 1000hr : circadian variation

Adjust time frame for shift workers

Wittert G. Curr Opin Endocrinol Diabetes Obes. 2014 ;21 239.

Confirmatory blood testing

Repeat total T

30% normalize on repeat

Serum LH: primary vs secondary testicular failure

Serum SHBG and calculated free T

Elevation: age, hyperthyroidism, liver

disease, anti-epileptic therapies

Suppression: obesity, insulin resistance,

androgen exposure

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

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)

Commonest chromosomal disorder 1:600 males

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

Klinefelter’s Syndrome – 47XXY

From: Nieschlag and Behre, 2007

gynecomastia

abdominal obesity

small testicular

volume

reduced body hair

horizontal pubic

hairline

varicose veins

narrow shoulders

Classical KS

in textbooks

Profound learning

difficulties



4

From: Nieschlag and

Behre, 2007

gynecomastia

abdominal obesity

small testicular

volume

reduced body hair

horizontal pubic

hairline

varicose veins

narrow shouldersNot always!!

may appear entirely normal and

adequately virilised when clothed

Classical KS

in textbooks

Profound learning

difficulties

From: Nieschlag and

Behre, 2007

gynecomastia

abdominal obesity

small testicular

volume

reduced body hair

horizontal pubic

hairline

varicose veins




Classical KS

in textbooks

~10,000 missed KS males in Australia

Failure to systemically examine male

genitalia : flaw in education & practice

From: Nieschlag and

Behre, 2007

gynecomastia

abdominal obesity

small testicular

volume

reduced body hair

horizontal pubic

hairline

varicose veins




Classical KS

in textbooks

~10,000 missed KS males in Australia

Failure to systemically examine male

genitalia : flaw in education & practice

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

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



5

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

Now it gets tricky.....

Low testosterone associated with

• Chronic disease

• Obesity

• Diabetes

• ? Age per se

When if ever is testosterone treatment warranted?

Now it gets tricky.....

Low testosterone associated with

• Chronic disease

• Obesity

• Diabetes

• ? Age per se

When if ever is testosterone treatment warranted?

All share common

non specific

symptoms with

androgen deficiency

1936 University of Washington Olympic Gold Medal Crew

Courtesy J Amory

1936 University of Washington Olympic Gold Medal Crew50-Year Reunion

Courtesy J Amory



6

Low “T” - How to Sell Disease Schwartz & Woloshin JAMA June 3rd 2013

‘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

affecting millions of men with low testosterone,

previously known as getting older.’

—The Colbert Report,1st December 2012

Healthy Man StudySartorius G et al Clin Endocrinol 2012 ;77:755

Testosterone

Age (years)

40 50 60 70 80 90

Se

rum

Te

sto

ste

ron

e (

nm

ol/

L)

0

5

10

15

20

25

30

35

40

n=325 men, 2900 serum specimens

35

Healthy Man StudySartorius G et al Clin Endocrinol 2012 ;77:755

Testosterone

Age (years)

40 50 60 70 80 90

Se

rum

Te

sto

ste

ron

e (

nm

ol/

L)

0

5

10

15

20

25

30

35

40

n=325 men, 2900 serum specimens

Serum T did not vary with age

T

Symptoms

Age

1

2

Barometer of

Health

hypothesis

2

1 2

1

Andropause

hypothesis

Disease

1 2

>60%

population

Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)

European Male Aging Study (EMAS) Relationship

between Age and Testosterone in 3220 Men

40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79



7

Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)

European Male Aging Study (EMAS) Relationship

between Age and Testosterone in 3220 Men

40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79

BMI <25

BMI 25-29

BMI ≥30

T

Symptoms

Age

2

Barometer of

Health hypothesis

2

1 2

1Andropause

hypothesis

Disease

2 A

22 B

T

Symptoms

Age

2

Barometer of

Health hypothesis

2

1 2

1Andropause

hypothesis

Disease

2 A

22 B? Testosterone

as adjunct in

management

Philosophy of Testosterone Treatment

Physiological replacement (‘natural therapy’)

Replicate normality in HYPOGONADAL men

Definition and identification of subjects

----------------------------------------------------------------------------

Pharmacological treatment (as a drug)

Dose for desired effect in EUGONADAL men

Risk : benefit ratio

Serum T 6.4 nM: maybe testosterone will help?

What is your goal?

Does testosterone

work?

Are there better

approaches?

When is enough

too much?



8

20 40

Serum testosterone rises as body weight fallsGrossmann M JCEM 2011, 96, 2341

Ageing, overweight men with type 2 diabetes and low T levels

→ lifestyle measures such as weight loss and exercise

Serum T

levels

Weight loss

Testosterone as a drug – emerging

therapeutic roles requiring RCT data

1. Metabolic syndrome & diabetes

2. Frailty – age or disease related sarcopenia

3. Depression

4. Cardiovascular health

Testosterone for Prevention of

Type 2 Diabetes in High Risk Men:

placebo-controlled RCTWittert G http://www.t4dm.org.au/

Hypothesis:

Reduce onset/reverse Type 2 DM in men with low T,

over and above a lifestyle program

Secondary endpoints:

• body composition

• systemic & vascular inflammation

• mood, QOL, psychosocial function

• adherence to the lifestyle program

~420 randomised

Target 1000

T

Symptoms

Age

2

Barometer of

Health hypothesis

2

1 2

1Andropause

hypothesis

Disease

2 A

22 B? Testosterone

as adjunct in

management

T

Symptoms

Age

2

Barometer of

Health hypothesis

2

1 2

1Andropause

hypothesis

Disease

2 A

22 BCompelling case

for RCTs on

specific endpoints

• efficacy

• safety

Current climate in TRT in aging men

Testosterone Replacement Therapy Faces FDA Scrutiny

Garnick M. JAMA , 2015: 313, 563

Disease Mongering of Age-Associated Declines in Testosterone and Growth Hormone Levels

Perls T & Handelsman DJ

J American Geriatrics Society, 2015 in press

PBS support threshold in men > 40 yr without a defined testicular or pituitary cause lowered to 6nM



9

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

RCTs

↑ CV events with high dose Te therapy in frail old men

Unconfirmed in another RCT in similar men

Meta-analysis: 3,000 mainly older men - ↑ in range of CV events ..many limitations to data

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 with known cardiovascular disease.

• Unstable cardiac disease or recent CV (within 6-12 months) constitute contraindications

Dr ‘No Testosterone’? Dr ‘Not first option and not

without deep reflection’

Managing Homer

• Lifestyle

– Diet

– Exercise

• Medical

– diabetes, hypertension, dyslipidemia

• Psychosexual issues

– Judicious use of PDE5 inhibitors

• Consideration of androgen therapy

– Realistic benefits – RCT data low quality

– Risks - ? cardiovascular

:

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

Testosterone no added benefit to sildenafil alone

Spitzer M Ann Intern Med 2012 57:681



10

Testosterone preparations

1940

1954

1977

1992

1995

1998

2004

2004

2002

2004

Testosterone preparations

Courtesy of M Zitzmann, Munster

Reandron

Testosterone replacement: individualized approach

Tailored to clinical setting

induction virilisation vs replacement in adulthood

Compliance

Age

0 1 2

Serum

Te

(nM)

10

20

30

T gel, patch,

axilla,cream

Days Weeks

0 2 4 6 8 10

T esters im

T undecanoate im‘Reandron’

T implant

Normal range

Testosterone Preparations

No oral or synthetic formulations Handelsman MJA 2012:196, 642 ↑

2↑↑012

Adoption of Reandron Australia 2006-2010

Issues with T undecanoate

15 years experience Europe, 10 yr in Australia

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 !

Post injection cough ~1:50 injection; mild/mod.

Midddleton Eur J Endocrinol 2015 Jan 30

Monitoring androgen therapy

‘Age-appropriate’ general medical care

lipids, blood pressure, weight

Special considerations:elderly: avoid long acting formulations - polycythemia

prostate health

cardiovascular health

sleep apnea – prior history or risk factors

Desire for fertility is a contraindication



11

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

Effect of testosterone replacement therapy on prostate cancer: systematic review & meta-analysis.

Cui Y Prostate Cancer Prostatic Dis 2014;17:132

22 RCTs, n= 2351: no increase in short-term

Long-term data are warranted

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

4. RCT data on testosterone as a ‘drug’ awaited

5. Testosterone therapy is readily monitored:

convenience = compliance

www.andrologyaustralia.org

Clinical summary guides

Courses for GPsaccredited education provider through RACGP

Course description Type

RACGP QI

&CPD Point

s

Younger male healthmale infertility, testicular cancer,

Klinefelters, PE, prostatitis

Online ALM

(Free)

40 Category

130 PRPD

points

Older male health androgen deficiency, erectile

dysfunction & co-morbid

disease, prostate disease.

Online ALM

(Free)

40 Category

130 PRPD

points

Aboriginal and

Torres Strait

Islander males

Tailored knowledge and skills to

initiate dialogue and

engagement

Male Health

Education

DVD

(Free)

4 Category 2 2 Core

points

Men’s sexual and

reproductive health

Postgraduate Unit Dept. of

General Practice, Monash Univ.

Distance

education

(Fee-

payable)

Contact the

Coordinator



12

Many thanks!

Acknowledgments Robert I. McLachlan, FRACP, PhD · Curatio PowerPoint TemplateControversies in Male...

Documents

Transcript of Acknowledgments Robert I. McLachlan, FRACP, PhD · Curatio PowerPoint TemplateControversies in Male...