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Sex Hormones in Relation to Movement, Mood, and Cognition Shalender Bhasin, MD Professor of Medicine, Boston University School of Medicine Chief, Section.

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Presentation on theme: "Sex Hormones in Relation to Movement, Mood, and Cognition Shalender Bhasin, MD Professor of Medicine, Boston University School of Medicine Chief, Section."— Presentation transcript:

1 Sex Hormones in Relation to Movement, Mood, and Cognition Shalender Bhasin, MD Professor of Medicine, Boston University School of Medicine Chief, Section of Endocrinology, Diabetes, and Nutrition Boston Medical Center Boston, MA

2 Testosterones Role in Evolutionary Selection of the Fittest Strength Visuospatial cognition Territoriality Aggression

3 Longitudinal Changes in Serum T Levels: Baltimore Longitudinal Study of Aging Testosterone (nmol/L) Age (Years) (177) (144) (151) (158) (109) (43) Harman SM, et al. J Clin Endocrinol Metab. 2001;86:

4 Epidemiological Data: Weak Association of Low T and Outcomes u Directly weakly associated with: –Muscle mass (Baumgartner 1998; Melton 2000), strength (Morley 2000), and self- reported physical function (MMAS 2005) – 2005) –Sexual desire (Beutel 2005) – –BMD, vBMD and bone geometry (Khosla 2005) u u Inversely associated with: – –CAD (Wu 2003; von Eckardstein 2003) – –Visceral fat (Seidell et al) – –Mortality (Shore et al 2006) u u Not associated with: – –Aging-related symptoms (TSjoen 2004) – –Prostate volume or LUTS (Schatzl 2000; Mohr 2007) – –Erectile Dysfunction (Korenman, 1996 ; Morley 1997) – –Depression indices (Seidman 2001; Barrett-Connor 2001; Schatzl 2000) – –

5 Testosterone and Feelings: Sexual Function in Older Men and Women

6 Epidemiology of Sexual Dysfunction in Middle- Aged and Older Americans: MMAS and NHLHS u million men in USA alone u 52% of men, years of age, have some degree of ED u Incidence rates : 600, ,000 cases annually MMAS (Feldman et al, J Urol 1994); NHLHS (Laumann et al, JAMA 1999)

7 Penile Erections Can Occur in the Absence of Testosterone But when the night was half-spent, he bethought him that he had forgotten in his palace somewhat which he should have brought with him, so he returned privily and entered his apartments, where he found the Queen, his wife, asleep on his own carpet bed embracing with both arms a eunuch of loathsome aspect and foul with grease and grime…So he drew his scimitar, and cutting the two in four pieces with a single blow, left them on the carpet…. Sir Richard Burton, The Arabian Nights, 1850 Sir Richard Burton, The Arabian Nights, 1850

8 Role of Testosterone in Spontaneous vs Induced Sexual Response u Compared to eugonadal men, hypogonadal men had : –Lower self-reported sexual activity, feelings and thoughts –Lesser number of spontaneous erections –Similar erectile response to visual erotic stimulus u Testosterone replacement for hypogonadal men: –Increased sexual feelings and thoughts, and sexual activity –Increased number of spontaneous erections –But did not change erectile response to visual erotic stimulus Spontaneous, but not stimulus-induced, erections are testosterone dependent are testosterone dependent Testosterone stimulates sexual thoughts and feelings Kwan et al, J Clin Endocrinol Metab 1983;57:557-62

9 T Improves Many Domains of Sexual Function in Androgen-Deficient Men u Spontaneous sexual thoughts and fantasies ( Kwan 1983, Bancroft 1985 ) u Frequency of spontaneous erections ( Kwan 1983, Cunningham 1990 ) u Overall sexual activity ( Wang 1996, 2004, Snyder 2000, Arver 1997 ) u Sexual arousal and enjoyment in response to erotic auditory stimulus ( 1997 ) ( Alexander 1997 ) u Frequency and duration of nocturnal erections ( Cunningham 1990, Carami 1990 )

10 Meta-analyses of T Effects on Men with Sexual Dysfunction u Moderate treatment effect on libido in men with low T levels (0.4, 95% CI 0.05, 0.8) u Inconsistent effects on erectile function; small effect in men with T (<300 ng/dL) u No effect on orgasmic and ejaculatory function u Inconsistent effects on response to PDE5 inhibitors (Shabsigh 2004; Aversa 2003) Caveats: imprecise estimates due to subject heterogeneity, variation in treatment regimens; incomplete reporting Jain et al, 2001; Montori et al 2005

11 Androgen Deficiency and ED are Two Independently Distributed Disorders u Frequency of low bioavailable testosterone levels is similar in middle-aged and older men with ED and without ED ( Korenman et al, JCEM 1990;71: ). u Six to 10% of men with ED have low testosterone levels ( Buvat and Lemaire J Urol 1997;158: )

12 Testosterone Might be Necessary for Achieving Optimal Penile Rigidity u T restores penile NOS activity in castrated rats ( Seo 1999; Baba 2000, Penson 1996; Lugg 1996 ). u T enhances penile blood flow; essential for venous occlusion ( Mills et al, 1997, 1998 ). u T has trophic effects on cavernosal smooth muscle and bulbospongiosus and ischiocavernosus muscles. ( Shabsigh 2000 )

13 Androgen Deficiency and ED are Two Independently Distributed Clinical Disorders AndrogenDeficiencyErectileDysfunction

14 COGNITIVE FUNCTION IN ELDERLY MEN WITH LOW T VS. NORMAL T COGNITIVE FUNCTION IN ELDERLY MEN WITH LOW T VS. NORMAL T Low T Normal T BVRTCVLT-ACVLT-DROTTRAILS A TRAILS B p <.001p <.01 p <.001p <.05 Test Score (Z-Score) Moffat, et al, J Clin Endocrinol Metab 87:5001, 2002

15 Testosterone Trials and Cognition: A Meta- analysis u Some trials have shown improvements in verbal memory, verbal fluency, and visuo-spatial cognition (Cherrier et al, Janowsky et al) u Meta-analysis revealed no overall effect on a number of dimensions of cognition: –Imprecise results, suboptimal power, heterogeneity Meta-analysis by Montori 2005 in Bhasin et al, JCEM 2005

16 T Dose Response in Young and Older Men: Change in Visual-Spatial Cognition T Dose (mg) Change in Visual- Spatial Cognition Scores T Dose Effect P = NS Age Effect P = NS

17 Testosterone, Mood, and Depression u Higher prevalence of low T levels in men with clinical depression ( Levitt et al, 1988; Seidman et al, 2002 ). u Testosterone replacement improves positive aspects of mood and decreases negative aspects of mood in healthy, hypogonadal men ( Wang et al, 1996; Alexander et al, 1998 ) and HIV-infected men ( Grinspoon et al, 2000; Rabkin et al, 2000 ). u Subjects with refractory depression receiving T had greater improvements in Hamilton Depression score than those on placebo ( Pope 2003 ).

18 Testosterone Effects on Physical Function and Mobility

19 Effects of A Supraphysiologic Dose of Testosterone on Fat–Free Mass in Healthy Men Change in Fat Free Mass ( Kg) PlaceboTestosteronePlaceboTestosterone No ExerciseExercise Bhasin S, Storer TW, et al, N Engl J Med 1996

20 Evidence of Testosterones Anabolic Effects u T replacement of hypogonadal men increases –FFM (2.3 kg, CI 1.2, 4.0) –muscle size, and –muscle strength (Bhasin 1997; Wang 2000; Snyder 2000) u T supplementation of HIV-infected men with weight loss increases: –body weight (1.5 kg, 0.03, 3.1) –LBM (1.3 kg, CI 0.2, 2.2) –muscle strength, and –some domains of HRQOL (Bhasin 1998, 2000; Grinspoon 1998, 2000)

21 Meta-analysis Plot of Lean Body Mass Change in Older Men Mean Difference in LBM (kg) Change between Placebo and T Groups Bhasin Nature CPEM 2005 T increases muscle mass

22 T Dose Response in Young and Older Men: Change in Fat Free Mass T Dose (mg) Change in FFM (kg) T Dose Effect P < Age Effect P = 0.22 Change in T X age P = 0.46 Bhasin et al JCEM 2005

23 T Dose Response in Young and Older Men: Change in Leg Press Strength T Dose (mg) Change in Leg Press Strength (lb) T Dose Effect P = Age Effect 0.84 Age X Change in serum T 0.29 Bhasin et al JCEM 2005

24 T Effects on Physical Function Snyder et al JCEM 1999 Meta-analysis: No significant effect on overall SF-36 HRQOL scoreNo significant effect on overall SF-36 HRQOL score Significantly greater improvement in physical function domain than placebo (0.5,95%CI 03, 0.9)Significantly greater improvement in physical function domain than placebo (0.5,95%CI 03, 0.9) Montori in: Bhasin et al, JCEM 2006 in press

25 Possible Reasons for Failure to Demonstrate Consistent Improvements in Measures of Physical Function u Inclusion of men who were not clearly hypogonadal u T dose and conc. relatively low u Studies performed in healthy older men, not in frail or impaired men u Problems with measurements of muscle performance and physical function: u Are older men relatively insensitive to the anabolic effects of androgens?

26 Testosterone Supplementation: Long- term Monitoring Concerns u Erythrocytosis u Prostate cancer and exacerbation of BPH u Cardiovascular disease u Fluid retention u Gynecomastia u Sleep apnea Morales A. Int J Impot Res. 2000;12(suppl):10. Abstract S11. Andropause Consensus Panel 2001; Bhasin S, J Androl 2001;22(5):718-31; Bhasin et al J Androl 2003

27 Testosterone Supplementation and Risk of Prostate Cancer: Issues u Many older men have microscopic foci of prostate cancer; T might make these subclinical foci grow. u Older men with low T levels may have prostate cancer (Morgentaler et al, 1996) u PSA levels increase after T administration (Meikle et al, 1997; Behre et al, 1994; Cooper et al, 1994). u Inherent bias towards detection of greater number of prostate events in T-treated men (Calof 2005) Adapted from Bhasin S, J Androl.2001;22: Bhasin et al, J Androl 2003

28 Meta-Analysis of Adverse Events in Testosterone Replacement Trials in Older Men Event Event Rate for testosterone Rate for placebo Odds Ratio 95% CI Prostate cancer 5/6432/ , 2.58 PSA>427/64314/ , 2.12 Biopsies21/6431/ , 4.37 Total prostate events (cancer, biopsies, PSA>4, increased IPSS score) 56/643 18/ , 3.00 Hct>50%35/6431/ , 3.28 All cardiac events ( A fib, MI, chest pain, CABG, CVA) 15/64314/ , 2.21 Death0/6432/ , 1.98 *computed using the Clopper-Pearson method ; random effects model

29 Testosterone and Cardiovascular Risk u Testosterone levels are lower in men with CAD than in healthy controls (Alexanderson 1996) u Physiologic T replacement has little or no effect on plasma HDLC in older men (Snyder et al, 1999; Tenover 2000; Sih et al, 1997) u Testosterone –improves coronary blood flow (Ong et al, 2000; English et al, 2000) –Reduces visceral fat and improves insulin sensitivity in middle aged men (Marin et al 1992) –Retards atherosclerosis progression in LDL-receptor deficient mice (Nathan et al, 2001) u T supplementation induces increase in LV mass (Casaburi unpublished)

30 Sophies Choice u Trade-off between beneficial effects of testosterone and the uncertainty about their adverse effects u Hypothesis: –SARMs and signaling effectors downstream of AR would provide better risk : benefit ratio

31 Mechanisms of Androgen Action: Targets for Drug Discovery

32 TE Dose mg/wk P = * * * * 600 vs 25mg: P< vs 50 mg: P< vs 125 mg: P< vs 25 mg: P< vs 25 mg: P< vs 125 mg: P< vs 25 mg: P<.05 Mechanisms of Androgen Action: Testosterone Induces Muscle Fiber Hypertrophy Change in Type II Fiber Area ( m 2 ) Change in Type I Fiber Area ( m 2 ) Sinha-Hikim et al, AJP Endo Metab 2002

33 Testosterone Increases Myonuclear and Satellite Cell Number SInha-Hikim et al, AJP 2003

34 DHT Dose-Dependently Stimulates Myogenic Differentiation of Mesenchymal Pluripotent Cells 0.3 nM 30 nM -DHT 1 nM3 nM w/o 1 st ab ** *** Immunocytochemistry Image Analysis Singh et al, Endocrinology 2003

35 Pluripotent Stem Cells A Model for Androgen Action on the Muscle Pre-adipocyte progenitor cell Mature Adipocyte Myoblast Myotube Satellite cell Fat cell lineageMuscle cell lineage MyoD MHC Desmin Pre- adipocyte Mesenchymal Stem Cells LPL PPARγ C/EBPα Bhasin et al, J Gerontol Med Sci 2003; Bhasin et al Nature CPEM 2005

36 β -catenin Cell Fate Myogenesis Adipogenesis Target genes TCF-4/LEF GSK-3 APC Axin Dsh AR Extracellular Wnt FrizzledCytoplasm LRP-5/6 β -catenin Wnt Signalling Pathway LiCl Integrin-linked kinases Nucleus BJS-1

37 PRKAA2, PRKWNK1: AMPK, insulin signaling DIPA: adipogenesis inhibitor RORA: nuclear hormone Receptor: interaction with MyoD NCOA3: hormone rec. coactivator, IGF signaling histone acetyltransferase, interacts with p300/CBP SYNCRIP: p68 kinase Insulin signaling IL6ST: gp130 cytokine Receptor / STAT SHARP: androgen receptor, Notch signaling TCF8: suppresses IL2 IGF1: Insulin-like growth factor 1 Placebo Testo TNFSF10: TRAIL / Apoptosis NFAT5: transcription factor, WNT signaling TCF4: beta-catenin binding transcription factor, Wnt signaling AR: androgen receptor SOS2: MAPK signaling SOS1: MAPK signaling Placebo Testo ATRX: helicase, chromatin remodelling TNFAIP6: hyaluronan-binding, TNF inducible TK2: mitochondrial dNTP kinase muscle activity DMPK: dystrophia myotonica protein kinase MADH5: SMAD5, TGFb signaling APOBEC3C: RNA editing Alterations in Intramuscular Gene Expression Associated with T Administration in HIV-Infected Men with Weight Loss Affymetrix U133A 2.0 chip Montano et al 2006

38 Anti-BJS-1 Antibody Blocks T Effects on Myogenic Differentiation BJS-1 T+Anti-BJS-1 T+BJ S1-Ab BJS-1 T+BSJ1 -Ab BJS-1 T+Anti-BJS-1 BJS-1 Singh et al (unpublished)

39 BJS-1 as an Example of T-Activated Target that Acts Downstream of AR, Promotes Muscle Mass and BMD, but Spares the Prostate BJS-1 Jasuja, Singh, Bhasin (unpublished) Fat-Free Mass Bone Mineral Density

40 SARM Discovery Based on Recognition of Conformational Change u Concern about prostatic effects in older men a major hurdle to the use of androgens as anabolic drugs u Current screening strategies are based on AR binding and transactivation assays and favor selection of partial agonists: a flawed strategy u Hypothesis: Three classes of ligands - androgen agonists, antagonists, and SARMs - confer distinct conformations to the androgen receptor protein upon binding to its ligand binding domain (LBD).

41 DHT-induced Changes in Emission Spectra AR AR + DHT lex = 278 nM (Tyrosines) lex = 290 nM (Tryptophans) AR AR + DHT

42 Tryptophan fluorescence spectra for AR LBD as a function of guanidinium hydrochloride concentration When G-HCl concentrations were varied tryptophan emission intensity varied in the presence of the three classes of ligands.

43 A High Throughput Screening Strategy Based on Conformational Change and FRET for SARM Development Jasuja and Bhasin unpublished

44 Conclusions u Total and free T levels decline with advancing age and are weakly associated with clinical outcomes. u Strong evidence that T supplementation increases: –skeletal muscle mass –maximal voluntary strength and leg power –decreases whole body and regional fat mass –libido u Weak evidence that –T therapy improves physical function, mood, and erectile function u Effects of T on clinical outcomes in older men with specific clinical syndromes: unknown u The long term risks: unknown

45 Institute of Medicine Expert Panel Report on the Future of Testosterone Research u Short-term RCTs of no longer than 1-year duration u Older men with specific syndromes, attributable to androgen deficiency, and low T levels u Replacement doses of testosterone u Adequately powered to determine efficacy using clinically relevant outcomes, rather than surrogate endpoints u Conduct larger trials to determine safety only if efficacy has been demonstrated Blazer et al, 2003; Snyder 2004; Barrett-Connor and Bhasin 2004

46 Mechanisms of Androgen Action u Androgens modulate differentiation of mesenchymal multipotent stem cells u Androgens regulate mesenchymal stem cell differentiation by promoting the association of AR with beta-catonin and activating TCF-4. Speculation u Mechanism-specific high throughput screening strategies based on recognition of unique conformational change provide powerful tools for discovery of SARMs that have the desired tissue-selectivity

47 Thank you to my partners: Exercise Physiology u Tom Storer u Nathan LeBrasseur u Linda Woodhouse Histomorphology u Indrani Sinha-Hikim Mechanisms u Rajan Singh u Monty Montano u Jorge Artaza u Ravi Jasuja u Nestor Gonzalez-Cadavid u Morris Res Coordinators u Connie Dzekov u Jeanne Dzekov u Rachelle Bross u Marjan Javanbakht hMSCs Ravi JasujaRavi Jasuja Clinical Investigators Atam Singh Olga Calof Helen Choi Behavioral Studies Peter Gray Ray Tricker Cardiovascular Markers Atam Singh Chris Roberts Conformational Studies Ravi JasujaRavi Jasuja Collaborators Richard Casaburi Kevin Yarasheski Fred Sattler James Kirkland Stefan Arver Harrison Pope Grant Support NIA, NIDDK, NICHD

48 King Testosterone O OH

49 Conceptual Framework and Feasibility of a High Throughput Screening Strategy for SARMs Jasuja and Bhasin unpublished

50 Lesson 3 for Drug Discovery u Mechanism-specific high throughput screening strategies based on recognition of unique conformational change provide powerful tools for discovery of SARMs that have the desired tissue- selectivity

51 Barriers for Regulatory Approval Uncertainties u How to operationalize the concept of individuals at risk for physical dysfunction and disability? u What outcomes should be used as measures of efficacy in clinical trials? T increases muscle mass and strength in older men, but improvements in physical function and clinical outcomes not demonstrated in men with physical dysfunction

52 Mechanisms of Androgen Action u Mechanism-specific high throughput screening strategies based on recognition of unique conformational change provide powerful tools for discovery of SARMs that have the desired tissue- selectivity

53 Lesson 2 for Drug Discovery: Wnt-Target Genes, such as BJS-1, are Attractive Candidates u Wnt signaling pathway: –a major determinant of mesenchymal stem cell differentiation –β -catenin at the crossroads of several signaling pathways: targets downstream would have greater specificity u Pharmacophores that activate Wnt signaling would promote myogenesis and inhibit adipogenesis. u Pharmacophores such as BJS-1 that activate Wnt-target genes downstream of AR would selectively increase muscle mass without affecting the prostate.

54 Testosterone Supplementation in Men with Refractory Depression u Study Design: Placebo-controlled, randomized, single- center, trial u Patients: 23 men with refractory depression on anti- depressant therapy, with serum T <350 ng/dL. u Treatment: Placebo or 10 g T gel daily X 8-weeks u Results: Subjects receiving T had greater improvements in Hamilton Depression score (-7.3) than those on placebo (-0.3). Pope et al, Am J Psych 2003;160:

55 Endocrine Society Expert Panels Guidelines for Monitoring During Androgen Therapy u At baseline, at 3, 6, 12 months after starting T therapy, monitor hemoglobin, PSA, DRE, AUA symptom score, sleep apnea scores u Obtain Urological consultation if: –Change in PSA of >1.4 ng/ml in any one year period ( Finasteride Study group, Gormley, 1992 ) –PSA velocity of >0.40 ng/ml/year ( Carter et al, 1995 ). Bhasin S, J Androl 2001;22:718-31; Bhasin et al, 2003; Endocrine Society 2005

56 An Investigators Prayer Oh Great Spirit: u Bless my partners (Tom Storer, Rajan Singh, Ravi Jasuja, Indrani-Sinha-Hikim, Linda Woodhouse, Jeanne and Connie Dzekov, Rich Casaburi, Jorge Artaza, Nestor Gonzalez-Cadavid, Kevin Yarasheski) for generating the data that make me look smarter than I am. u Please, soften the hearts of the reviewers of our grants and manuscripts, and keep us funded!

57 The US Endocrine Society Expert Panels Recommendations: 2005 u Recommended against a general clinical policy of offering testosterone therapy to all older men with low testosterone levels. (1| ). u Suggested that clinicians consider T therapy on an individualized basis to older men with consistently low T levels and significant symptoms of androgen deficiency, after discussion of the risks and benefits (2| ) u Suggested clinicians offer T therapy to men with low T levels and low libido and/or erectile dysfunction in order to improve libido (2| ) and erectile function (2| ).

58 *p<.05 vs control; + p<.05 RT+T vs RT Meters * *+ TESTOSTERONE TRIAL CHANGE IN 6-MINUTE WALKING DISTANCE IN 6 MONTHS Testosterone treatment improved 6-minute walking distance to a greater extent than placebo in older men approaching frailty.

59 2 nd order derivative spectra follows the bears and lamberts law; the DHT induced perturbations in tyrosine and tryptophan residues can be calculated as below: a b Evidence that Androgen Binding Induces Specific Conformational Change

60 Inherent Bias Towards Overestimation of Prostate Events in Testosterone-Arms of Clinical Trials u Prostate biopsies usually triggered by PSA increments in clinical trials u PSA increments are more likely in T-treated men than in placebo-treated men. u Therefore, T-treated men likely to undergo greater number of prostate biopsies, resulting in detection of a greater number of subclinical prostate cancers. Calof and Bhasin J Gerontol 2005

61 Are Older Men Less Sensitive to the Anabolic Effects of Androgens?

62 T Regulates Many Domains of Sexual Function in Men u T replacement of hypogonadal men increases: –Spontaneous sexual thoughts and fantasies (Kwan 1983, Bancroft 1985) –Frequency of spontaneous erections (Kwan 1983, Cunningham 1990) –Overall sexual activity (Wang 1996, 2004, Snyder 2000, Arver 1997) –Sexual arousal and enjoyment in response to erotic auditory stimulus ( 1997) –Sexual arousal and enjoyment in response to erotic auditory stimulus (Alexander 1997) –Attentiveness to erotic stimulus (Alexander 1997) –Frequency and duration of nocturnal erections (Cunningham 1990, Carami 1990) u T does not affect response to VES (Davidson 1978; Kwan 1979)

63 The Role of Testosterone in Penile Erections But when the night was half-spent, he bethought him that he had forgotten in his palace somewhat which he should have brought with him, so he returned privily and entered his apartments, where he found the Queen, his wife, asleep on his own carpet bed embracing with both arms a eunuch of loathsome aspect and foul with grease and grime…So he drew his scimitar, and cutting the two in four pieces with a single blow, left them on the carpet…. Sir Richard Burton, The Arabian Nights, 1850

64 Team Testosterone u Clinical Investigators –Shalender Bhasin –Norm Mazer –Philip Knapp –Andrea Coviello –Atam B. Singh –Olga Calof u Fellows -MaClara Padero -Ricky Mac -Helen Choi u Mechanisms –Rajan Singh –Ravi Jasuja –Jorge Artaza –Nestor Gonzalez-Cadavid –John Flanagan –Carl Morris u Exercise Physiology –Tom Storer –Linda Woodhouse u Stable Isotope Work –Kevin Yarashesji u Lipids –Petar Alaupovic u Insulin Sensitivity –Tom Buchanan –Stan Hsia u Co-investigators –Rich Casaburi –Mitch Harman –Keith Beck

65 Team Testosterone u Clinical Research Team Director: Linda Woodhouse u Research Coordinators: -Tina Davidson -Connie Dzekov -Jeannie Dzekov -Veronica Sanatana -Jeff Celzada u Exercise Physiology Laboratory Director: Thomas W. Storer Tech: Lynn Magliano u Body Composition –Linda Woodhouse –Thomas W. Storer u Hormone Assays –Indrani Sinha-Hikim –Mag Que

66 Is Testosterone the Fountain of Youth? T T T T

67 Myocardial O 2 Supply/Demand CHF O2ml/min ischemia ischemia CHF Maximum O2 extraction Maximum coronary vasodilation 60% occlusion 80% occlusion Hagl, Bas Res Cardiol 1977;72:344 Spahn, J Thor Card Surg 1993;165:694 Anesth Analg 1995;80:219 Burch GE, Dis Chest 1965;48:225-32

68 Dose-Selection: Trade-Off Between Adverse Effects and Beneficial Effects u Very substantial skeletal muscle remodeling is possible in healthy, older men with androgen administration. u Trade-off between the dose, anabolic effects and adverse events u Best trade-off was achieved at 125 mg/week TE dose: –Very low frequency of AEs –Serum T levels in the high normal range –Average 4.2 kg increase in FFM –Average 28 kg gain leg press strength u SARMs that are preferentially anabolic but do not have the adverse effects of T would be useful in sarcopenia associated with aging and chronic illness.

69 β -catenin Cell Fate Myogenesis Adipogenesis Target genes TCF-4/LEF GSK-3 APC Axin Dsh AR Extracellular Wnt FrizzledCytoplasm LRP-5/6 β -catenin Wnt Signalling Pathway LiCl Integrin-linked kinases Nucleus

70 Role of 5-Alpha Reductase and Aromatase in Mediating Androgen Action on Muscle 5-Alpha Reductase 5-Alpha Reductase –-Very low levels of 5-alpha reductase activity in muscle (Bartsch et al, 1980) –-Patients with 5-alpha reductase mutations have normal muscle development at puberty (Imperato-McGinley et al, 1976) –-Finasteride-treated men do not undergo muscle loss Aromatase Aromatase –-Aromatase KO mice have decreased muscle mass and increased fat mass (Fisher et al, 1998)

71 T Dose-dependently Improves Overall Sexual Function Scores in Older Men Overall ANOVA P= Change in Overall Sexual Function Testosterone Dose (mg/week) Gray et al 2005 in press

72 T Dose Response in Young and Older Men: Change in Hemoglobin T Dose (mg) Change in Hemoglobin (g/L) T Dose Effect P < Age Effect P < 0.001

73 Effect of T Replacement on LV and RV Mass in Men with COPD LEFT VENTRICULAR MASS RIGHT VENTRICULAR MASS Exercise–+ –+ –+ –+ TE – –++ – –++

74 Change in Specific Tension PlaceboTestosteronePlaceboTestosterone No Exercise Exercise Percent Change from Baseline overall ANOVA, p=0.001 * p<0.001 vs Placebo, No Exercise p<0.001 vs Testosterone, No Exercise p<0.001 vs Testosterone, No Exercise * *

75 Changes in Erectile Function Overall ANOVA P=0.024Overall ANOVA P=0.380 Change in Waking Erections Change in Spontaneous Erections Testosterone Dose (mg/week)

76 T Dose Response in Young and Older Men: Change in Plasma HDL Cholesterol T Dose (mg) Change in HDL Cholesterol (mg/dL) T Dose Effect P = Age Effect P = 0.67 Change in T level X Age effect P = 0.86

77 TE Dose mg/wk P = * * * * 600 vs 25mg: P< vs 50 mg: P< vs 125 mg: P< vs 25 mg: P< vs 25 mg: P< vs 125 mg: P< vs 25 mg: P<.05 Mechanisms of Androgen Action: Testosterone Induces Muscle Fiber Hypertrophy Change in Type II Fiber Area ( m 2 ) Change in Type I Fiber Area ( m 2 ) Sinha-Hikim et al, AJP Endo Metab 2002

78 Myonuclear Number / mm mg 300 mg 600 mg Satellite Cell Number / mm Testosterone Enanthate Dose Levels * ** * P = 0.04 P = 0.03 Changes in Myonuclear and Satellite Cell Number After Treatment with GnRH Agonist and Testosterone Sinha-Hikim et al, AJP Endo 2003

79 DHT Dose-Dependently Stimulates Myogenic Differentiation of Mesenchymal Pluripotent Cells 0.3 nM 30 nM -DHT 1 nM3 nM w/o 1 st ab ** *** Immunocytochemistry Image Analysis Singh et al, Endocrinology 2003

80 CDHTTDHT+ BicT + Bic Pos Nuclei/Total Nuclei x 100 * ** ### Stimulation of MyoD Expression in 10T1/2 cell by T and DHT is inhibited by Bicalutamide C vs. DHT p<0.01 C vs. T p<0.05 DHT vs. DHT + Bic p<0.001 T vs. T + Bic p<0.001 DHT (10nM) Blank T (30nM) control DHT (10nM) + Bic (100nM)T (30nM) + Bic (300nM) 400X Immunocytochemistry Image Analysis Singh et al, 2003

81 Fat cells /10 fields Dose-Dependent Inhibition of Adipogenesis by Androgens in Mesenchymal Pluripotent Cells Singh et al, 2003

82 G APDH - PPAR- - C/EBP 40 kD 30 kD 42 kD 52 kD : DHT (nM) DHT Inhibits the Expression of PPAR-gamma and C/EBP-alpha in C3H10T1/2 Cells Singh et al, Endocrinology 2003

83 A Dominant Negative TCF4 cDNA Construct Blocks Testosterone Effects on Myogenesis in Mesenchymal Pluripotent Cells MHC+ Myotubes/hpf

84 Effect of T Supplementation on Bone Mineral Density in Older Men StudyDurationT DoseResults Tenover 3 years150-mg TE/2 wksIncr spinal and fem BMD Snyder3 years6-mg scrotal ptachIncr. spinal BMD Kenny1 yearNongenital patchIncr. Femoral BMD

85 Summary and Conclusions u T supplementation in eugonadal men, older men and men with chronic diseases and low T levels increases: –skeletal muscle mass –maximal voluntary strength and leg power –decreases whole body and regional fat mass u T effects on physical function and health-related outcomes (disability, falls, well-being, QOL): unknown u Uncertainties: –The long term risks: unknown –No consensus on how to operationalize the concept of individuals at risk for disability –Do women have different T dose response relationships?

86 Mechanisms of Androgen Action u Androgen increase muscle mass and reduce fat mass by promoting differentiation of mesenchymal pluripotent stem cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage. u Androgens regulate mesenchymal stem cell commitment by activating Wnt signaling. Speculation u Models that incorporate H:R binding, AR conformational change, thermodynamics, DNA binding, and in vitro myogenic activity would provide a more precise prediction of SARM activity. u SARMs hold great promise for treatment of sarcopenia associated with aging and chronic illness, and for fat accumulation syndromes.

87 Adverse Events Associated with T Administration in Older Men: A Meta-Analysis Criteria for inclusion in the systemic review: u Placebo-controlled, RCT u Middle-aged or older men (>45 years of age) u Medically stable individuals free of specific diseases u Replacement doses of testosterone or its esters Number of studies included = 17 Number of subjects in placebo group = 427 Number of subjects in T group = 643

88 Operationalizing the Concept of Individuals at Risk for Disability u Frieds multi-dimensional construct of frailty (2001) –Predicts risk of falls, disability, and mortality –Affects only 7% of men and women >65 –Difficult to operationalize in clinical trials –Identifies a group with high morbidity and mortality u Gill: Battery of physical function measures ( 1998, 1999 ) u Guralnik: lower extremity function ( 1994, 1995 ) u Sarcopenia defined in terms of appendicular skeletal muscle mass ( Melton 2000; Baumgartner 1998 )

89 Sarcopenia as an Excellent Biomarker of Aging u Is predictive of clinical outcomes: falls, fractures, and disability (Melton 2001; Baumgartner 1998) u In cross-species comparisons, sarcopenia is predictive of biological age and mortality (Herndon 2002; Guarente 2000) u Responsive to anabolic interventions (Bhasin 2001; Snyder 1999; Tenover 1992, 2000; Roubenoff 2002) u Can be measured precisely and accurately (Kim et al, 2002; Heymsfield 1998) u Significant changes demonstrable over short durations

90 What Outcomes Should be Measured in Clinical Trails of Anabolic Therapies? u Measures of muscle mass (DEXA, D2O) u Measures of muscle performance –Muscle strength, power, and fatigability u Measures of Physical Function u Health-related outcomes –Sense of well-being –Energy/fatigue –Affectivity balance –Physical activity –Disability scale

91 Summary and Conclusions 1. Different androgen-responsive functions have different T dose-response relationships 2. Anabolic effects of T are correlated with T dose and conc. 3. Older men are NOT less sensitive to anabolic effects of T. 4. Older men differ from young men in other aspects: -Older men have higher serum T levels: decreased clearance -Older men have higher frequency of Hct> 54%, edema, and prostate events -Older men had a greater increase in Hg/Hct

92 Edema and CHF During Testosterone Administration u Leg edema observed largely in older men receiving supraphysiological doses u Occurred within 1-4 weeks of starting treatment u Was associated with SOB in two men who developed leg edema; echocardiograms in these two men revealed normal ejection fractions and evidence of diastolic dysfunction u Pre-existing heart disease?

93 We have learned much, but much remains unknown… u T supplementation of older men with low T levels increases FFM, muscle size, and strength, but we do not know whether it can induce meaningful gains in physical function, risk of disability, sense of well being, HRQOL. u Long term safety unknown u Uncertainty about how to operationalize the concept of individuals at risk for disability u Do women have different dose-response relationships than men?

94 We have learned much, but much remains unknown… u Mechanisms –How do androgens increase muscle mass? –Are anabolic effects AR-mediated? Non- genomic effects –The kinetics and thermodynamics of T:AR interaction –The role of 5-alpha reduction and aromatization

95 Effects of Testosterone and Resistance Exercise on Lean Body Mass (DEXA) in HIV+ Men with Low T Levels No Exercise Exercise PlaceboTestosteronePlacebo+ExerciseTestosterone+Exercise Change in FFM (kg) * p<0.005 vs zero change * * Bhasin et al, JAMA 2000

96 Androgen Therapy: Contraindications u Prostate cancer u Breast cancer u BPH with severe symptom score or bladder outlet obstruction u Erythrocytosis with hematocrit >52% u Severe sleep apnea u Severe (class IV) congestive heart failure Adapted from Bhasin, S, J Androl 2001;22:718-31; Andropause Consensus Panel, 2001 Tremblay J, Morales A. Aging Male. 1998;1:

97 Issues in SARM Development u Can androgen administration improve muscle performance and produce meaningful improvements in health-related outcomes? u What patient populations provide the best opportunities for initial efficacy trials? u Uncertainty about measures of muscle performance and physical function that can be used as outcome measures in efficacy trials u Lack of good correlation between Kd and in vivo potency –Better measures of hormone:receptor interaction u Lack of good in vitro bioassays that are predictors of in vivo anabolic efficacy u Lack of good animal models of sarcopenia that can be used to demonstrate beneficial effects of SARMs

98 T Dose Response in Young and Older Men: Change in Youngs Mania Rating Score T Dose (mg) Change in Youngs Mania Score

99 Are Older Men Relatively Insensitive to Androgen Effects? u Many changes during the aging process such as decreased sexual function, osteoporosis, and muscle loss are similar to those associated with androgen deficiency. u Total and free T conc. in older men are lower than younger men, but most healthy older men have serum T in eugonadal range.

100 Hypotheses-2 3. Older men are not insensitive to the anabolic effects of T on lean body mass, muscle size and strength.

101 Compliance with Study Treatment Young Men: Young Men: –Only one man in 126 mg dose missed one TE injection –GnRH agonist: 100% Older Men Older Men –TE: 100% –GnRH agonist: 100%

102 Study Design Sample Size: men in each of the 5 treatment groups Sample Size: men in each of the 5 treatment groups Treatment Duration: 20 weeks Treatment Duration: 20 weeks Exercise stimulus was controlled. Exercise stimulus was controlled. Protein and energy intake Protein and energy intake 35 Kcal/kg/day, 1.5 g protein/kg/day 35 Kcal/kg/day, 1.5 g protein/kg/day Compliance verified by 3-day food records and 24-hr phone recall Compliance verified by 3-day food records and 24-hr phone recall

103 T Dose Response in Young and Older Men: Change in Sexual Activity & Desire T Dose (mg) Change in Sexual Activity & Desire Scores T Dose Effect P = NS Age Effect P = NS

104 T Dose Response in Young and Older Men: Change in PSA T Dose (mg) Change in PSA (ng/ml) T Dose Effect P = 0.58 Age Effect P = 0.65 Change in T level X Age Effect P = 0.13

105 Testosterone Effects on HRQOL: Rationale u Lean body mass is an important determinant of HRQOL in HIV-infected individuals ( Wilson et al, 1999 ) u Testosterone improves LBM and HRQOL in HIV- infected men (Grinspoon et al, 1998) u Aging-associated impairment of physical function is associated with significant decrease in overall HRQOL (Wier et al). u TRT improves rehabilitation outcomes in ill, older men ( Bakhshi et al, 2000 ).

106 T Dose Response in Young and Older Men: Change in Free T Change in Free T (pg/mL) TE (mg) T dose effect, P< Age effect, P<0.0001

107 Prevalent Dogma: Protein Synthesis as the Target of Androgen Action This hypothesis does NOT explain: 1. The reciprocal decrease in fat mass 2. The observed increase in myonuclear and satellite cell number 3. AR localization localization in precursor cells mostly outside the muscle fiber Pluripotent Stem Cell Differentiation as the Target of Androgen Action: An Alternative Hypothesis Pluripotent Stem Cell Differentiation as the Target of Androgen Action: An Alternative Hypothesis Bhasin et al, J Gerontol 2003

108 Effect of Age in Men on Body Fat, Lean Body Mass, and Weight Weight Lean Body Mass Body Fat Age (years) Body Composition Component (kg) Forbes GB, Reina JC, Metab 1970;19:653

109 Androgen Receptor is Expressed in Satellite Cells AR Immunostaining CD34 AR CD34+AR

110 T (nM) MHCII GAPDH- - Az ** *** mRNA * ** * 215 kDa 40 kDa Myo D mRNA by Real-Time PCR MHCII Protein by Western Androgens Upregulate MyoD and MHC Expression

111 Forest Plot of Mean Difference for Fat Mass Change Mean Difference Study Grinsp 2000 Bhasin 1998 Storer 2004 Grinsp 1998 Grunfeld 2004 Bhasin 2000 Combined Symbol Combined Individual

112

113 Prostate Events

114 Cardiovascular Events

115 Hematocrit Greater than 50%

116 Testosterone Effects on HRQOL: Rationale u Lean body mass is an important determinant of HRQOL in HIV-infected individuals ( Wilson et al, 1999 ) u Testosterone improves LBM and HRQOL in HIV- infected men (Grinspoon et al, 1998) u Aging-associated impairment of physical function is associated with significant decrease in overall HRQOL (Wier et al). u TRT improves rehabilitation outcomes in ill, older men ( Bakhshi et al, 2000 ).

117 Effects of Testosterone Replacement in Older Men with Low or Low Normal T Study Treatment Regimen in Body Comp in Body Comp in Muscle Function in Muscle Function Comments Subjects Sih, et al 1997 Morley, et al 1993 Tenover, et al 1992 TE 100 mg/wk for 3 months y/o T<400 ng/dL 1.8 kg in FFM No in FM No in grip strength Mild in PSA and HCT y/o BT<75 ng/dL TE 200 mg/2 wks for 3 months No in FM or body weight in grip strength in grip strength Healthy, y/o BT<60 ng/dL TC 200 mg/2 wks for 12 months No in body comp 4-5 kg in grip strength - No in PSA in HCT

118 Effects of Testosterone Replacement in Older Men (cont) Study Treatment Regimen in Body Comp in Body Comp in Muscle Function in Muscle Function Comments Subjects Tenover2000 Snyder, et al 1999 Urban, et al 1995 TE weekly for 4 wks to T to ng/dL Healthy, >65 y/o T <480 nd/dL Body comp not reported hamstring & quadriceps strength hamstring & quadriceps strength 2-fold in muscle protein synth. rate Healthy, >65 y/o Scrotal T patch 6 mg/day for 3 yrs LBM kg LBM kg FM 3 kg No in knee extension & flexion Healthy, older men TE 150 mg/2 wks for 3 yrs FFM FFM FM FM Improved grip strength Improved perception of physical function -

119 Control DHT 10nM T and DHT induce nuclear translocation of -catenin 40x T 100nM DHT 10nM+BIC 100nM BIC 100nM Red: -catenin (Texas Red) Blue: counterstain (DAPI) Red: -catenin (Texas Red) Blue: counterstain (DAPI)

120 Effects of Testosterone Replacement in Older Men (cont) Urban et al 2002 Older men with T<17 nmol/L TE variable dose Incr. FFM Incr. muscle strength Incr. IGF-1 and AR expression Kenny et al, older men bioT <4.4 nmol/L T patch 5 mg/d or placebo +1 kg Incr. In FFM, 2% decr. in FM Incr. In muscle strength Incr. BMD

121 GnRHTE Expected Group Agonist Dose T conc. I+25 mg175 ng/dL II+50 mg350 ng/dL III+125 mg800 ng/dL IV+300 mg1400 ng/dL V+600 mg2500 ng/dL Study Design

122 Summary of Adverse Events u Numerically, greater number of adverse events and SAEs in older men than younger men: not statistically significant. u None of the younger men had a SAE. u The AE profile was different in young and older men: –Young men had a higher frequency of acne than older men. –Older men had higher frequency of Hct >54%, edema, CHF, and prostate events than young men. –Most frequent causes of treatment discontinuation in older men were Hct >54% and leg edema; these AEs were dose related. –Therefore, DSMB discontinued 600 mg dose in older men in Dec

123 Dose-Selection: Trade-Off Between Adverse Effects and Beneficial Effects u Higher the dose, greater the anabolic effects, and higher the frequency of adverse events u Best trade-off was achieved at 125 mg/week TE dose; this dose was associated with: –Very low frequency of AEs –Serum T levels in the high normal range –Average 4.2 kg increase in FFM –Average 28 kg gain leg press strength

124 Role of Testosterone in Spontaneous vs Induced Sexual Response u Compared to eugonadal men, hypogonadal men had : –Lower self-reported sexual activity, feelings and thoughts –Lesser number of spontaneous erections –Similar erectile response to visual erotic stimulus u Testosterone replacement for hypogonadal men: –Increased sexual feelings and thoughts, and sexual activity –Increased number of spontaneous erections –But did not change erectile response to visual erotic stimulus Spontaneous, but not stimulus-induced, erections are testosterone dependent are testosterone dependent Testosterone stimulates sexual thoughts and feelings Kwan et al, J Clin Endocrinol Metab 1983;57:557-62

125 Forest Plot of Mean Difference for FFM Change Mean Difference Study Bhasin 1998 Storer 2004 Bhasin 2000 Grinsp 1998 Combined Symbol Combined Individual

126 Mechanisms of Anabolic Effects on the Skeletal Muscle u The increase in muscle strength is proportional to the increase in muscle mass; specific tension does not change (Storer 2004) u T supplementation is associated with dose-dependent increase in hypertrophy of both type I and II fibers (Sinha-Hikim 2002). u T-induced muscle hypertrophy is accompanied by an increase in the number of myonuclei and satellite cells (Sinha-Hikim 2003)

127 T Supplementation in Older Men: The Issue of Our Times u T prescription sales in the USA in 2004 >600 million dollars; 26- fold increase since 1993 u >1000 T-related stories in the media

128 Change in Total T in Young and Older Men Treated with GnRH-A + TE Change in T (ng/dL) TE (mg) T dose effect, P< Age effect, P<0.0001

129 T Dose Response in Young and Older Men: Change in Fat Mass (DEXA) T Dose (mg) Change in Fat Mass (kg) T Dose Effect P < Age effect P<0.001

130 Age-Related Decline in Lean Mass and Muscle Strength (BLSA; Roy et al 2002) Age (years) Leg and Arm Lean Mass (kg) Quadricepes and Biceps Strength (N) Age (years)

131 Powerful Demographic Trend Towards Aging of Human Populations Physical dysfunction Sexual dysfunction Cognitive impairment Poor HRQOL Increased health care $$$$$$ Growing populations of older men and women around the globe

132 Is Testosterone the Fountain of Youth? T T T T

133 Testosterone and Cognition: Intervention Studies StudyInterventionPatients Results AlexanderT replacementhypogonadal Incr. verbal men fluency Van GoozenT replacementTrans-sexual Incr.Spatial cognition JanowskyT replacementHealthy older Incr. spatial men cognition JanowskyT replacementHealthy older Improved men working memory CherrierT replacementOlder menImproved verbal memory and fluency

134 Testosterone Effects on Mood u Clinical Experience: –Hypogonadal men report marked improvement in sense of wellbeing, energy, and mood after initiation of T therapy u T therapy improves positive aspects of mood and decreases negative aspects of mood in hypogonadal men (Wang et al, JCEM 1996) u No RCTs in older men

135 Total Serum T Levels in Young and Older Men Treated with GnRH-A + TE Serum T (ng/dL) TE (mg) T dose effect, P< Age effect, P< Bhasin et al JCEM 2005

136 T Effects on Bone Outcomes u No data on bone fractures u Two trials of 3-years duration showed a moderate effect on lumbar bone density (0.4, CI 0.1,0.7) (Snyder 1999; Amory 2004) u Ruled out a moderate treatment effect on femoral neck bone density (0.0, CI -0.3, 0.3) Montori 2005

137 Rationale for T Supplementation in Older Men: Hypotheses u T levels decline with advancing age. u Low T associated with adverse health outcomes u T supplementation improves physical, sexual, cognitive function, QOL and other health-related outcomes u Testosterone administration is SAFE.

138 Epidemiological Data: Weak Association of Low T and Outcomes u Directly associated with: –Muscle mass (Baumgartner 1998; Melton 2000), –Strength of knee extension (Morley 2000) –Self-reported physical function (MMAS 2005) – 2005) –Sexual desire (Beutel 2005) – –BMD, vBMD and bone geometry (Khosla 2005) u u Inversely associated with: – –CAD (Wu 2003; von Eckardstein 2003) – –Visceral fat (Seidell et al) – –Mortality (Shores et al 2006)

139 Inconsistent or No Association u u Aging-related symptoms (TSjoen 2004) u u Prostate volume or LUTS (Schatzl 2000) u u Erectile Dysfunction (Korenman, 1996 ; Morley 1997) u u Depression indices (Seidman 2001; Barrett- Connor 2001; Schatzl 2000)

140 Effects of T Therapy on Erectile Function and Libido Bolona et al. (unpublished)

141 Sexual Function: A Complex, Multi-Component System

142 Effects of Castration on Life Span and Cardiovascular Mortality u Studies of castrati singers –Nieschlag (1993): no difference in life span between 50 castrated and 50 intact opera singers –Jenkins (1998): no difference between life span of 25 castrated and 25 intact singers u Studies of castrated, institutionalized men with behavioral problems ( Hamilton and Mestler, 1969 ) –Median life span greater in castrated men (69 yrs) than intact men (56 yrs) u Models of life span extension have low levels of sex hormones and growth factors ( Bartke et al, 2002 )

143 Testosterone Increases Attentiveness to Erotic Stimuli u Testosterone replacement therapy in hypogonadal men increases: –Attentiveness to sexual stimulus in dichotic listening/selective attention task Alexander et al, Horm Behav 1997;31: David: Previous slide note on bottom of slide says testosterone does not enhance stimulus-induced erection. This slide talks about sexual arousal (presumably erection) in response to auditory stimulus? David: Previous slide note on bottom of slide says testosterone does not enhance stimulus-induced erection. This slide talks about sexual arousal (presumably erection) in response to auditory stimulus?

144 Testosterone Effects on Cognition u Question: To determine effects of T on cognitive abilities in healthy older men u Design: Placebo-controlled, double-blind, randomized. u Groups: TE 100 mg weekly vs. placebo X 6-wks u Results: improvements with TRT in –spatial memory (recall of a walking route) –spatial ability (block construction) –verbal memory (recall of a short story) Cherrier et al, Neurology 2001;57:80-8

145 T Dose Response in Young and Older Men: Change in Hamilton Depression Rating T Dose (mg) Change in Hamilton Depression Score Age effect = NS Dose Effect = NS

146 Meta-analysis Plot of Fat Mass Change in Older Men Mean Difference in Fat Mass (kg) Change between Placebo and T Groups Bhasin Nature CPEM 2005 T deceases fat mass

147 TESTOSTERONE TRIAL EFFECTS OF TESTOSTERONE ON PHYSICAL FUNCTION IN OLDER MEN (Page, S. T. et al. J Clin Endocrinol Metab 2005;90: )


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