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Testosterone New Insights for its Application in Men and Women : 

Testosterone New Insights for its Application in Men and Women Uwe D Rohr Universitätsfrauenklinik Abt. für Gynäkologische Endokrinologie und Sterilitätsbehandlung Medizinische Universität Wien Österreich

Testosterone : 

Testosterone Production In males produced by Leydig Cells 6-7 mg / day In females by conversion of DHEA to T in ovaries 200-300 µg Name (68 Years old) „testo“ = testes „ster“ = sterol „one“ = ketone Moleculare Structure of Testosterone

Testosterone : 

Testosterone Scientific research for 150 years 1927 isolation from bull testes (McGee) 1937 chemical synthesis by 3 groups Butenandt rewarded Nobel Prize 1937 1969 DHT (Dehydrotestsoterone) discovered 2003 Nongenomic and Genomic Action of Androgen Receptor

History of Testosterone in Therapy : 

History of Testosterone in Therapy 1918 Vasectomy Therapy by Eugen Steinach (1861-1944) in Vienna 1927 First Definition of „Male Climacteric“ by A. Hoche in Germany 1946 Heller and Myers „controlled clinical trial“ T for male climacteric symptoms 1946 first description of male climacteric: Nervousness, sweating, decreased potency Ernest Hemingway T replacement for ten years Longest patient history

Testosterone Metabolism : 

Testosterone Metabolism Estradiol Testosterone 5α-dihydrotestosterone 5α- Reductase Aromatase 1937 discovered discovered 1968

Testosterone Increase Inhibiting Degredation with an Aromatase Inhibitor Anastrozol (Aromasin®) : 

Testosterone Increase Inhibiting Degredation with an Aromatase Inhibitor Anastrozol (Aromasin®) Bioavailable Testoterone (ng/dL) 300 200 100 0 Placebo 2/week 1/day Leder et al, JCEM 2004 n = 37 elderly men each group

Slide 7: 

15 jähriges Mädchen Dihydrotestosterone Inhibition Dermal Acne Treatment with a new 5-reductase Inhibitor U Rohr, unreported results 2004

Slide 8: 

Dihydrotestosterone Inhibition local Acne Treatment with a new 5-reductase Inhibitor Tag 1 Tag 15 Tag 30 U Rohr, unreported results 2004

2 types of androgenic Alopecia : 

2 types of androgenic Alopecia Stratum Corneum 20 µm Dermis Blood Perfused Ca 2000 µm Reduction of Mitosis Rate By androgens Reduction of Capillaries by Diabetes Type in men < 35 y 2. Type in men > 35 y Reduction of Mitosis Rate By DHT Reduction of Skin Capillaries by Age These men often have women in their families Suffering from Polycycstic ovaries (Insulin sensitivity and high testosterone levels)

Morbus Addison(Bronzehautkrankheit) : 

Morbus Addison(Bronzehautkrankheit) Störung der Nebennierenrinde Niedriger Cortsionspiegel Fehlen von DHEA Auto-Immunerkrankungen Androgen-Mangel Psychosen Muskelschwund Bei DHEA – Gabe hohe Libido Wirksamkeit von Androstendione Estradiol und Testosteron

Morbus Addison(Bronzehautkrankheit) : 

Morbus Addison(Bronzehautkrankheit) Störung der Nebennierenrinde Niedriger Cortsionspiegel Fehlen von DHEA Auto-Immunerkrankungen Androgen-Mangel Psychosen Muskelschwund Bei DHEA – Gabe hohe Libido Wirksamkeit von Androstendione Estradiol und Testosteron „Patient No 1“: John F Kennedy

Slide 12: 

Circadian and Circannual Rhythms of Testosterone In women U Rohr Maturitas 2002

Testosterone and Male Age : 

Testosterone and Male Age n=1114 men Oettel, Naturwissenschaften 2004

Serum Cortisone and Male Age : 

Serum Cortisone and Male Age Oettel, Naturwissenschaften 2004

Testosteroneas an Index of Male Hypogonadism : 

Testosteroneas an Index of Male Hypogonadism Age Percent of Men With low Levels of Testosterone NEJM ; 2004

Synonyms for Androgen Deficiency : 

Synonyms for Androgen Deficiency Andropause Male climacteric Aquired male hypogonadism Late onset hypogonadism Androgen decline in aging males (ADAM) Partial androgen decline in aging males - PADAM

Improved Physical Strength in Men with Ischemic Heart Disease after Testosterone Therapy : 

Improved Physical Strength in Men with Ischemic Heart Disease after Testosterone Therapy Changes in distance achieved in the shuttle walk test n=12 men with ischemic Heart Disease R D Jones, Heart 2004

Testosterone reduces Myocardial Infarction : 

Testosterone reduces Myocardial Infarction Reduces Infarction Rate 25% Via a non-genomic Mechanism Evidence of a direct Calcium Antagonism Action Improve Haemodynamic effects Reduces Severity of a Myocardial Infarction R Jones, The Biochemical Society 2004

Testosterone Treatment and Physical Appearance : 

Testosterone Treatment and Physical Appearance Rohr, Maturitas 2002 Crypt orchid Man Crypt orchid Man After 2 Years Treatment with Testosterone

Dose Dependent Effect of Testosterone on Regional Adipose Tissue : 

Dose Dependent Effect of Testosterone on Regional Adipose Tissue Woodhause et al. J of Endocrinol and Metabolism 2004 80 60 40 20 0 -20 % Change of total Body AT Mass Testosterone Dose (mg/week) 25 50 125 300 600

Depression und Dementia : 

Depression und Dementia The Scream (or The Cry) 1893 Edvard Munch

Free testosterone and risk for Alzheimer disease in older men : 

Free testosterone and risk for Alzheimer disease in older men Coefficients, hazard ratios, and 95% CI from time dependent proportional hazards of AD predicted by FTI, with and without covariates Resnick, National Institute of Aging, USA Neurobiology 2004 Coefficient HR 95% CI Sole predictor FTI - 0.89 0.41 0.34 0.50 With covariates FTI - 0.30 0.74 0.57 0.96 Age, y 0.06 1.07 1.04 1.09 Ever smoke 0.62 1.86 1.39 2.50 BMI 0.09 0.92 0.87 0.97 Diabetes 0.41 0.67 0.44 1.00 Any cancer diagnoses 0.19 1.21 0.78 1.87

Slide 23: 

Reduced Testosterone in Brain : A direct Risk of developing Alzheimer in Men JAMA Sept. 2004 Testosterone In the brain Post mortem (ng/cm3 tissue) n = 12 per each group

Testosterone vs Age in Women : 

Testosterone vs Age in Women Age 24 h mean Plasma Testosterone (ng/dL) Zumoff et al, J. Clinical Endocrinology and Metabolism 1995

Slide 25: 

Testosteron has impact on well being

Testosterone improves muscle Contractability and Strength in Clitoris : 

Testosterone improves muscle Contractability and Strength in Clitoris Kim et al International Journal of Impotence Research 2004

Potential Risk with Testosterone : 

Potential Risk with Testosterone Respiratory: Sleep Apnea Skin Acne Local reactions to topical reagents Breast Gynecomastia Cardiovascular Coronary Artery Disease : no evidence Lipids : neutral effect Erythrocytosis : Common with injections Prostate Benign prostatic hyperplasia: rare Prostate cancer : unproven Testes Atrophy and infertility : common NEJM ; 2004

Potential Risk with Testosterone Replacement Therapy : 

Potential Risk with Testosterone Replacement Therapy NEJM ; 2004

Prostate cancer and Testosterone : 

Prostate cancer and Testosterone Increase in PSA Prostate cancer (number / total number) NEJM ; 2004

Prostate Cancer and Testosterone : 

Prostate Cancer and Testosterone 1 out of 486 men under Testosterone replacement After 1 year treatment developed prostate cancer What is the rate in men without Testosterone replacement Oettel, Naturwssenschaften 2004

Hormone Replacement in Women : 

Hormone Replacement in Women Estrogen + Progesterone protects Endometrium of Uterus Estrogen and Testosterone protect Breast Tissue? reduces Mitosis Rate Reduces Breast Endothel Tissue in Monkey Labrie , Menopause 2003

Comparison of Injectable and transdermal Testosterone by a Patch : 

Comparison of Injectable and transdermal Testosterone by a Patch The Journal of Clinical Endocrinology & Metabolism 1999

Multiple Consecutively Application of Testosterone by a Gel : 

Multiple Consecutively Application of Testosterone by a Gel n = 26 males Rolf et al. European Journal of Endocrinology (2002) 146 673–679

No Interpersonal Testosterone Transfer after Topical Application : 

No Interpersonal Testosterone Transfer after Topical Application Rolf et al. European Journal of Endocrinology (2002) 146 673–679

Buccal Delivery of Testosterone : 

Buccal Delivery of Testosterone EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004)

Repeated Buccal Delivery of Testosterone : 

Repeated Buccal Delivery of Testosterone EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004)

Dose Dependent Pharmacokinetics of oral TestosteroneAndriol Testocaps® : 

Dose Dependent Pharmacokinetics of oral TestosteroneAndriol Testocaps® W J of Urology 2004 Free Testosterone (ng/ ml) 10 8 6 4 2 0 80 mg 40 mg 20 mg 0 2 4 6 8 10 12 14 16 18 20 24 Time ( h )

Steady State Development of Testosterone and Route of Delivery : 

Steady State Development of Testosterone and Route of Delivery 1 w 2w 3w oral transdermal with a gel injectable 2m 3m UD Rohr, 2004

Recommendations for Monitoring Testosterone-Replacement Therapy : 

Recommendations for Monitoring Testosterone-Replacement Therapy Rhoden , NEJM 2004 Time Base line Determine history with standardized questionnaire Determine tests for base line testosterone, PSA hematocrit or hemoglobin Perform prostate biopsy if PSA level above 4.0 ng /ml (2% of all men) Follow up Perform efficacy evaluation after 1-2 month Monitoring every 3 month in the first year Monitor Gynecomastia Perform blood tests for testosterone, hematocrit or hemaglobin and PSA Prostate biopsy if substantial change in PSA

Clinical Indication to keep for Testosterone innormal age-related Values : 

Clinical Indication to keep for Testosterone innormal age-related Values Men Reduce Cardiovascular Risk Maintain body weight Maintain “well being” Reduce Alzheimer Risk Women Reduce Cardiovascular Risk Reduce Breast Cancer Risk Keep body weight Maintain well being and libido Maintain bone health Rohr, 2004

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