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.