T – Time

The Testosterone Revolution for Men
Dr Malcolm Carruthers Medical Director Men’s Health Centre 20/20 Harley Street, London, W1G 9PH
carruthers@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
Ernst Laqueur Adolf Butenandt Leopold Ruzicka

1935 Testosterone Isolated, Named, and Synthesised

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, NSW

Testosterone: use, misuse and abuse Medical 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 Heart
Professor Kevin Channer Consultant 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 Arver Dierector 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 Drive
Professor Abdul Traish Director of Urological Research, Boston University ‘Female arousal disorder: Sexual function and androgen deficiency’ Dr Adrian Zentner Medical Director, National Well Men and Women Too Programme Australia. Dr Clem Williams Medical Director Dundarave Medical Clinic, West Vancouver, Canada. ‘Clinical experiences with TRT in women’

Testosterone and the Penis
Professor Abdul Traish Director 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

Rita Hayworth Iris Murdoch

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

Loss of Dendrites

Amyloid Core of Neuritic Plaque

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

Male
Brain
Right Cerebral Cortex Thicker, HypothalamicLimbic nuclei

Female
Brain
Left Cerebral Cortex Thicker, Corpus Callosum Larger

Skills
Spatial Specialisation Focussed Dyslexic Colour-blind

Skills
Verbal Multi-tasking Diffuse Emotional Intuitive

Importance of ADAM Diagnosis 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 the Adult Male (ADAM)
Definition: An absolute or relative deficiency of testosterone or its metabolites according to the needs of that individual at that time in his life.
(c.f. insulin in diabetes mellitus)

The Multiple Causes of Androgen Deficiency
CEREBRAL 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 Obesity
OBESITY Lower SHBG, TT, FT, and DHEA levels, but higher E2 and insulin levels than the nonobese 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 Scales
AUTHOR Werner Heller Reiter Carruthers Carruthers Tremblay Heinemann SCALE TITLE Male Clim. Male Clim. IDUT ACL Short ACL CAS AMS YEAR STUDY BEGAN 1939 1944 1953 UKAS 1989 Web1996 1998 1999 NUMBER IN STUDY 273 23 100 1,500 1533 300 992 RESPONSES Yes/No Yes/No 0 -12 0-4 0 - 4 Yes/No 1 - 5. SYMPTOMS: Erectile Dysfunction 90 ++ ++ 84 83 ++ 88 Libido/sex drive/desire 81 ++ ++ 82 87 ++ 84 Fatigue/energy reduced 80 ++ + 78 94 + 80 Depression 77 + ++ 62 88 + 75 Anxiety/nervousness 91 ++ ++ ++ 85 + 69 Memory/concentration 76 + + 42 90 + Irritability/anger 80 + + 57 85 + 72 Aches/pains joints 33 + 57 83 77 Sweating esp. night 18 + 50 63 + 66 Vasomotor/flushes 46 + 27 + Ageing/older than years 43 55 59

Problems With Sampling
Circadian and Seasonal Variation, Diet, Fasting and Alcohol, Physical Activity and Posture, Sample Preservation and Storage

Medical Problems
Illness, Stress, Sexual Activity, Smoking

Analytical Problems
Methodology, Specificity and Interference, Accuracy and Precision

Interpretation Problems
Log-normal distribution, Age-related Levels Androgen receptor polymorphism Up- and down-regulation Interactions of other hormones and drugs

Androgen Deficiency in the Adult Male (ADAM) Definition: An absolute or relative deficiency of testosterone or its metabolites according to the needs of that individual at that time in his lif

Validity of Androgen Assays
Problems With Sampling
Pulsatile,Circadian and Seasonal Variation, Diet, Fasting and Alcohol, Physical Activity and Posture, Sample Preservation and Storage

Medical Problems
Illness eg metabolic syndrome, Stress, Sexual Activity, Smoking

Analytical Problems
Methodology, Specificity and Interference, Accuracy and Precision

Interpretation Problems
Log-normal distribution, Age-related Levels Androgen Resistance

Lower Limits TT in Relation to PBS Cut-off Point
Sikaris,K., Handelsman,DJ. et al. J Clin.Endocrinol.Metab. 2005,90,5928-36
14 12 Total Testosterone (nmol/l) 10 8 6 4 2 0 GCMS A B C D E F G Laboratory Low er Limits

PBS Manufacturers Arithmetic Logarithmic

Blood Testosterone Threshold for Androgen Deficiency Symptoms

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

‘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

Sites of Androgen Resistance
T → DHT or E2
AR AR

AR

AR

ARE

ARE

Translation and post-translational factors
Modified from Nussey,S.S., Whitehead, S.A. 2001

Sensitivity to T Feedback ↑

Age and the
GNRH ↓ Oestrogens ↑ GH ↓

Regulation of Testosterone Synthesis
Mean LH Pulse Amplitude ↓

DHEA ↓

Testicular Degeneration

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

Circadian rhythm of testosterone is lost in aging men
Total testosterone (ng/ml) 30 8 * p<0.05; ** p<0.01 (young vs. old)

** ** **

**
25 7

** *

* * *

*

*

**
YOUNG MEN

6 20

5 15 4 nmol/l 08.00 12.00 16.00 20.00 Time
Bremner et al. J Clin Endocrinol Metab 1983;56:1278-1281 OLD MEN

24.00

04.00

08.00

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

Application of Testogel®

• • •

once daily, preferably in the morning on clean, dry and intact skin on upper arm, shoulder and / or abdomen - not on the genitals

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 Treatment and 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
Total - 214 Reactions in 185 Patients (3Deaths)
Cutaneous + Local Reaction 117 Implant + Injection complications 90, Rash 15 Psychiatric + General Endocrine + Metabolic + Musculo-skeletal Gastrointestinal + Liver + Respiratory Vascular Neurological + Eye Neoplasms + Urological 27 17 16 15 13 9 Aggression 6,Depression 3,(Suicide 1) Muscle cramps 3, Arthralgia3, Hirsutism 1, Diabetes1 Diarrhoea 7, Nausea 3, Abdominal pain 3,Jaundice 2 Cardiac 8, CVA2, DVT 4, Embolus 1 Paraesthesia 6,Headache 6(OD-CVA1) ?Prostate 2, (Sarcoma 1), Breast 1, Priapism 2,Test.Pain 2,Renal failure 1

Costs of Treatment/Month (Medication only – other costs to medical system and patients not included)

Testosterone Preparation Testosterone Pellet Implants Injected T-Esters (Sustenon) Injected T-Undecanoate (Nebido) Oral T-Undecanoate (Andriol) T-Gel (Testogel) Scrotal T-Cream (Andromen)

Cost (£) % Abs. Theory Practice 20 10 22 27 33 8 100 * 100 * 100 ** 10 ** 15 *** 70 **** *** * **** ** *** ***

Key Messages Testosterone 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.