T – TimeThe Testosterone Revolution for Men

Dr Malcolm CarruthersMedical Director Men’s Health Centre

20/20 Harley Street, London, W1G 9PHcarruthers@men’shealthcentre.co.uk

Why Testosterone is Important

King of Hormones – Hormone of Kings

High-T males: Potentates to Presidents

NOW

The Hormone of Preventive Medicine!

A Hundred Years of Hormones

1905 Sir Ernest Starling – Introduced Word ‘Hormone’

70 Years of Testosterone

1935 Testosterone Isolated, Named, and Synthesised

Ernst Laqueur Adolf Butenandt Leopold Ruzicka

Symptoms of Testosterone Deficiency

• Potency Reduced• Libido Reduced• Drive Reduced• Depression• Memory Loss• Aging• Aches and Pains• Sweats• Hot Flushes• Dry Skin

What Do You Call It?

Male Climacteric

Male Menopause

Idiopathic Hypergonadotrophic Hypogonadism

Late-Onset Hypogonadism

Andropause

ADAM: Androgen Deficiency in the Adult Male

“T” The Hormone of Preventive Medicine

• Affects body development• Provides energy & drive

• KEEPS YOU FIT, ACTIVE and ATTRACTIVE - FROM CRADLE TO GRAVE

• “It’s not the man in your life that’s important, it’s the life in your man!”

• Mae West

Ageing and Life Course

Ageing and Life Course

Importance of Testosterone Replacement Therapy

Adding years to life

and

Life to years

To Treat or Not to Treat -That is the Question

Against: David J. Handelsman, Professor of Andrology, ANZAC Research Institute, Concord Hospital, Sydney, NSWTestosterone: use, misuse and abuseMedical Journal of Australia, October 2006, vol 185, 436-9.

‘Testosterone is among the oldest drugs in medicine. It has a long efficacy and safety record for its prime role of androgen replacement therapy in men with androgen deficiency.’‘Androgen misuse is the systematic over-prescribing for unproven medical indications. Misuse is increasingly evident for male ageing ("andropause") and some other clinical conditions. Further trials for new indications for androgens require reliable safety data, but rising costs may make it increasingly attractive to circumvent the need for evidence by promoting off-label mass marketing.’

For: The rest of this talk, and the many researchers who have given evidence in favour of the proven need, safety and efficacy of it’s use.

The ISSAM Recommendations

American Endocrine Society Recommendations

Testosterone and the HeartProfessor Kevin ChannerConsultant Cardiologist, Sheffield Hallam University, UK.

‘Testosterone a Tonic for the Heart’

• No link between High-T and heart disease.• Men with heart disease have lower T levels than

those without.• TRT lower heart attack risk factors, including

cholesterol, neutral fat, high blood pressure and blood clotting factors.

• TRT increases blood flow to the heart.• TRT improves angina.

Metabolic Syndrome

(Syndrome-X)

A Growth Industry

Testosterone, Obesity and Diabetes

Professor Stefan ArverDierector of Andrology Centre, Karolinska Institute, Stockholm

‘Testosterone and Metabolic Changes in Men with Abdominal Obesity’

• Severe obesity is not a benign condition.• It can lead to ‘Metabolic Syndrome’ with raised

cholesterol and neutral fat, blood pressure, heart disease and insulin resistance causing diabetes.

• Testosterone is low in Metabolic Syndrome.• TRT improves body composition, reducing

abdominal obesity and increasing muscle mass. It prevents and treats Metabolic Syndrome.

Woody Allen -Love is the Answer

But Sex Raises Some Interesting Questions

Testosterone and Sex DriveProfessor Abdul TraishDirector of Urological Research, Boston University

‘Female arousal disorder:Sexual function and androgen deficiency’

Dr Adrian ZentnerMedical Director, National Well Men and Women Too Programme Australia.

Dr Clem WilliamsMedical Director Dundarave Medical Clinic,West Vancouver, Canada.

‘Clinical experiences with TRT in women’

Testosterone and the PenisProfessor Abdul TraishDirector of Urological Research, Boston University

• Testosterone deficiency damages the penis and prevents the chemical changes needed for erection.

• TRT , as well as restoring sex drive, reverses these changes, and improves erectile function in the majority of cases.

• TRT works well with Viagra, Levitra and Cialis where these are needed (Dream Team)

Life expectancy and Alzheimer’s Disease

Ronald Reagan

Iris Murdoch

Rita Hayworth

Charlton Heston

Duration of AD can be 20 years or more, but

typically 4-8 years

(The long good-bye)

Brain Changes in Alzheimer’s Disease

Neurofibrillary Tangles and Neuritic Plaques

Amyloid Core of Neuritic Plaque

Loss of Dendrites

Chemical Andropause and Amyloid-ß PeptideSam Gandy et al, JAMA, 2001, Vol. 285, No.17

Male Female

BrainRight CerebralCortex Thicker,Hypothalamic-Limbic nuclei

SkillsSpatial

SpecialisationFocussedDyslexic

Colour-blind

BrainLeft Cerebral

Cortex Thicker,Corpus Callosum

LargerSkillsVerbal

Multi-taskingDiffuse

EmotionalIntuitive

Importance of ADAMDiagnosis and Treatment

Great personal, social and economic, as well as medical,

importance in aging populations world-wide

Promotion of ‘Active Aging’ and prevention and delaying of physical

and mental disability

Adding years to life and life to years

Androgen Deficiency in theAdult Male (ADAM)

Definition:An absolute or relative deficiencyof testosterone or its metabolitesaccording to the needs of thatindividual at that time in his life.

(c.f. insulin in diabetes mellitus)

The Multiple Causes of Androgen DeficiencyCEREBRAL CORTEX

Age, Stress (Underload and Overload), Drugs

HYPOTHALAMUS AND PITUITARY

Age, GNRH decreased, and more sensitive to feedback, Prolactin, Drugs

TESTES

Age, Impaired development, Infections, Alcohol, Diet, Xeno-estrogens and Anti-androgens, Temperature, Trauma, Drugs

TARGET ORGANS

Age, SHBG, Receptor anomalies, Reduction and Down- regulation, Androgen Resistance Syndrome, (ARS)

Connective tissue thickening, Drugs,

Diet and ObesityOBESITY Lower SHBG, TT, FT, and DHEA levels, but higher E2 and insulin levels than the non-obese

SLIMMING

Low CHO Low Protein TT and FT and Insulin lowered, and SHBG rises

High Protein, Low Fibre(Atkins) TT and FT raised, SHBG reduced

Andropause Symptom ScalesAUTHOR Werner Heller Reiter Carruthers Carruthers Tremblay HeinemannSCALE TITLE Male Clim. Male Clim. IDUT ACL Short ACL CAS AMSYEAR STUDY BEGAN 1939 1944 1953 UKAS 1989 Web1996 1998 1999NUMBER IN STUDY 273 23 100 1,500 1533 300 992RESPONSES Yes/No Yes/No 0 -12 0 - 4 0 - 4 Yes/No 1 - 5.SYMPTOMS:Erectile Dysfunction 90 ++ ++ 84 83 ++ 88Libido/sex drive/desire 81 ++ ++ 82 87 ++ 84Fatigue/energy reduced 80 ++ + 78 94 + 80Depression 77 + ++ 62 88 + 75Anxiety/nervousness 91 ++ ++ ++ 85 + 69Memory/concentration 76 + + 42 90 +Irritability/anger 80 + + 57 85 + 72Aches/pains joints 33 + 57 83 77Sweating esp. night 18 + 50 63 + 66Vasomotor/flushes 46 + 27 +Ageing/older than years 43 55 59

Problems With SamplingCircadian and Seasonal Variation, Diet,Fasting and Alcohol, Physical Activity and Posture, Sample Preservation and StorageMedical ProblemsIllness, Stress, Sexual Activity, SmokingAnalytical ProblemsMethodology, Specificity and Interference,Accuracy and PrecisionInterpretation ProblemsLog-normal distribution, Age-related LevelsAndrogen receptor polymorphismUp- and down-regulationInteractions of other hormones and drugs

Androgen Deficiency in theAdult Male (ADAM)

Definition:An absolute or relative

deficiencyof testosterone or its

metabolitesaccording to the needs of thatindividual at that time in his

lif

Problems With SamplingPulsatile,Circadian and Seasonal Variation, Diet,Fasting and Alcohol, Physical Activity and Posture, Sample Preservation and StorageMedical ProblemsIllness eg metabolic syndrome, Stress, Sexual Activity, SmokingAnalytical ProblemsMethodology, Specificity and Interference,Accuracy and PrecisionInterpretation ProblemsLog-normal distribution, Age-related LevelsAndrogen Resistance

Validity of Androgen Assays

Lower Limits TT in Relation to PBS Cut-off PointSikaris,K., Handelsman,DJ. et al. J Clin.Endocrinol.Metab. 2005,90,5928-36

0

2

4

6

8

10

12

14

GCMS A B C D E F G

Laboratory Lower Limits

Tota

l Tes

tost

eron

e (n

mol

/l)

PBSManufacturersArithmeticLogarithmic

Blood Testosterone Threshold forAndrogen Deficiency Symptoms

‘Each person had a consistent testosterone threshold for androgen deficiency symptoms that differed markedly between individuals’ Kelleher,S.; Conway,A.J.; Handelsman,D.J. J Clin.Endocrinol.Metab. 2004,89,3813-17

PBS ------------------------------ PBS ------------------------------ PBS

AR AR

AR AR

ARE ARE

Sites of Androgen Resistance

T → DHT or E2

Translation and post-translational factors

Modified from Nussey,S.S., Whitehead, S.A. 2001

Age and the

Regulation

of

Testosterone

Synthesis

Modified from Nussey,S.S., Whitehead, S.A. 2001

Mean LH Pulse Amplitude ↓

GNRH ↓

Oestrogens ↑ GH ↓

Sensitivity to T Feedback ↑

DHEA ↓

Testicular Degeneration

Circadian rhythm of testosterone is lostin aging men

Bremner et al. J Clin Endocrinol Metab 1983;56:1278-1281

8

7

6

5

4

08.00 12.00 16.00 20.00 24.00 04.00 08.00

Total testosterone (ng/ml)

YOUNG MEN

OLD MEN

**

** **

****

**

*

* **

* *

Time

* p<0.05; ** p<0.01 (young vs. old)

30

25

20

15

nmol/l

ARS LONGA – VITA BREVIS

(Freely translated means ‘Androgen Resistance Syndrome long-term shortens life’ )

Ref. Low Serum Testosterone and Mortality in Male Veterans, M.Shores et al, Arch.Intern.Med.,2006;166:1660-5.

Testosterone Treatment

• Testosterone Pellet Implants• Testosterone Undecanoate Injections (Nebido)• Testosterone orally - Restandol• Transdermal Creams – DHT and Testosterone• Transdermal Gels – Androgel and Testogel• Danazol

• once daily, preferably in the morning

• on clean, dry and intact skin• on upper arm, shoulder and / or

abdomen- not on the genitals

Application of Testogel®

Feldmann RJ,.Maibach HI. Regional variation in percutaneous penetration of 14C cortisol in man. Journal of Investigative Dermatol. 1967;48:181-3.

Amounts of steroid absorbed by skin in different areas compared to forearm

Conclusions on Testosterone Treatmentand Prostate Cancer

(Mr Mark Feneley – Senior Lecturer in Urologic Oncology, Institute of Urology,

London)

• No evidence that testosterone treatment causes prostate cancer

• Pre-screening is important prior to testosterone therapy

• PSA monitoring identifies prostate cancer at an early stage

• Prostate cancer identified by PSA is potentially curable

Adverse Reactions to Testosterone 1963-2002 (Yellow Card)

UK Medicines Control Agency

Aggression 6,Depression 3,(Suicide 1)27Psychiatric + General

Cardiac 8, CVA2, DVT 4, Embolus 115Vascular

Implant + Injection complications 90, Rash 15

117Cutaneous + Local Reaction

?Prostate 2, (Sarcoma 1), Breast 1, Priapism 2,Test.Pain 2,Renal failure 1

9Neoplasms + Urological

Paraesthesia 6,Headache 6(OD-CVA1)13Neurological + Eye

Diarrhoea 7, Nausea 3, Abdominal pain 3,Jaundice 2

16Gastrointestinal + Liver + Respiratory

Muscle cramps 3, Arthralgia3, Hirsutism 1, Diabetes1

17Endocrine + Metabolic + Musculo-skeletal

Total - 214 Reactions in 185 Patients (3Deaths)

Costs of Treatment/Month(Medication only – other costs to medical

system and patients not included)Testosterone Preparation Cost (£) % Abs. Theory Practice

Testosterone Pellet Implants 20 100 * ***Injected T-Esters (Sustenon) 10 100 * *Injected T-Undecanoate (Nebido) 22 100 ** ****Oral T-Undecanoate (Andriol) 27 10 ** **T-Gel (Testogel) 33 15 *** ***Scrotal T-Cream (Andromen) 8 70 **** ***

Key MessagesTestosterone Treatment is:

• Simple, if you don’t make it complicated

• A very effective form of treatment• An economic form of treatment• Gives many grateful patients• Safe, if you take a few simple

precautions• A powerful form of preventive medicine

Why is it T-Time?• 70 years of experience with testosterone treatment

shows it’s safe, effective and not rocket science.• Its being recognised that symptoms rather than blood

tests are better for diagnosing testosterone deficiency.• Testosterone deficiency can be due to resistance to its

action as well as a low level.• Resistance in the medical profession to its therapeutic

use is being overcome.• It is becoming accepted as an important factor in heart

disease, obesity, diabetes, erection problems and the causes of physical and mental ageing.

• It is an economic form of treatment that can add life to years, as well as years to life.