Presentation on theme: "Sex Hormones in Relation to Movement, Mood, and Cognition"— Presentation transcript:
1Sex Hormones in Relation to Movement, Mood, and Cognition Shalender Bhasin, MDProfessor of Medicine, Boston University School of MedicineChief, Section of Endocrinology, Diabetes, and NutritionBoston Medical Center Boston, MA
2Testosterone’s Role in Evolutionary Selection of the Fittest StrengthVisuospatial cognitionTerritorialityAggression
3Testosterone (nmol/L) C9Longitudinal Changes in Serum T Levels: Baltimore Longitudinal Study of Aging2018(177)(144)(151)16Testosterone (nmol/L)(109)14(43)(158)12Longitudinal effects of aging on date-adjusted testosterone. Linear segment plots for testosterone vs. age are shown for men with testosterone values on at least two visits. Each linear segment has a slope equal to the mean of the individual longitudinal slopes in each decade, and is centered on the median age, for each cohort of men from the second to the ninth decade. Numbers in parentheses represent the number of men in each cohort. Segments show significant downward progression at every age with no significant change in slopes for testosterone over the entire age range.1030405060708090Age (Years)Harman SM, et al. J Clin Endocrinol Metab. 2001;86:Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86:
4Epidemiological Data: Weak Association of Low T and Outcomes Directly weakly associated with:Muscle mass (Baumgartner 1998; Melton 2000), strength (Morley 2000), and self-reported physical function (MMAS 2005)Sexual desire (Beutel 2005)BMD, vBMD and bone geometry (Khosla 2005)Inversely associated with:CAD (Wu 2003; von Eckardstein 2003)Visceral fat (Seidell et al)Mortality (Shore et al 2006)Not associated with:Aging-related symptoms (T’Sjoen 2004)Prostate volume or LUTS (Schatzl 2000; Mohr 2007)Erectile Dysfunction (Korenman, 1996 ; Morley 1997)Depression indices (Seidman 2001; Barrett-Connor 2001; Schatzl 2000)
5Testosterone and “Feelings”: Sexual Function in Older Men and Women
6MMAS (Feldman et al, J Urol 1994); NHLHS (Laumann et al, JAMA 1999) Epidemiology of Sexual Dysfunction in Middle-Aged and Older Americans: MMAS and NHLHS25-30 million men in USA alone52% of men, years of age, have some degree of EDIncidence rates : 600, ,000 cases annuallyMMAS (Feldman et al, J Urol 1994); NHLHS (Laumann et al, JAMA 1999)
7Penile 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
8Role of Testosterone in Spontaneous vs Induced Sexual Response Compared to eugonadal men, hypogonadal men had:Lower self-reported sexual activity, feelings and thoughtsLesser number of spontaneous erectionsSimilar erectile response to visual erotic stimulusTestosterone replacement for hypogonadal men:Increased sexual feelings and thoughts, and sexual activityIncreased number of spontaneous erectionsBut did not change erectile response to visual erotic stimulusSpontaneous, but not stimulus-induced, erectionsare testosterone dependentTestosterone stimulates sexual thoughts and feelingsKwan et al, J Clin Endocrinol Metab 1983;57:557-62
9T Improves Many Domains of Sexual Function in Androgen-Deficient Men 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(Alexander 1997)Frequency and duration of nocturnal erections(Cunningham 1990, Carami 1990)
10Meta-analyses of T Effects on Men with Sexual Dysfunction Moderate treatment effect on libido in men with low T levels (0.4, 95% CI 0.05, 0.8)Inconsistent effects on erectile function; small effect in men with T (<300 ng/dL)No effect on orgasmic and ejaculatory functionInconsistent effects on response to PDE5 inhibitors (Shabsigh 2004; Aversa 2003)Caveats: imprecise estimates due to subject heterogeneity, variation in treatment regimens; incomplete reportingJain et al, 2001; Montori et al 2005
11Androgen Deficiency and ED are Two Independently Distributed Disorders Frequency of low bioavailable testosterone levels is similar in middle-aged and older men with ED and without ED (Korenman et al, JCEM 1990;71:963-70).Six to 10% of men with ED have low testosterone levels (Buvat and Lemaire J Urol 1997;158:1764-9)
12Testosterone Might be Necessary for Achieving Optimal Penile Rigidity T restores penile NOS activity in castrated rats(Seo 1999; Baba 2000, Penson 1996; Lugg 1996).T enhances penile blood flow; essential for venous occlusion(Mills et al, 1997, 1998).T has trophic effects on cavernosal smooth muscle and bulbospongiosus and ischiocavernosus muscles.(Shabsigh 2000)
13Androgen Deficiency Erectile Dysfunction Androgen Deficiency and ED are Two Independently Distributed Clinical DisordersAndrogenDeficiencyErectileDysfunction
14COGNITIVE FUNCTION IN ELDERLY MEN WITH LOW T VS. NORMAL T 0.3BVRTCVLT-ACVLT-DROTTRAILSATRAILSB0.20.1Test Score (Z-Score)Low TNormal T-0.1-0.2-0.3p < .001p < .01p < .01p < .001p < .05p < .05-0.4Moffat, et al, J Clin Endocrinol Metab 87:5001, 2002
15Testosterone Trials and Cognition: A Meta-analysis Some trials have shown improvements in verbal memory, verbal fluency, and visuo-spatial cognition (Cherrier et al, Janowsky et al)Meta-analysis revealed no overall effect on a number of dimensions of cognition:Imprecise results, suboptimal power, heterogeneityMeta-analysis by Montori 2005 in Bhasin et al, JCEM 2005
16T Dose Response in Young and Older Men: Change in Visual-Spatial Cognition ScoresT Dose Effect P = NSAge Effect P = NST Dose (mg)
17Testosterone, Mood, and Depression Higher prevalence of low T levels in men with clinical depression (Levitt et al, 1988; Seidman et al, 2002).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).Subjects with refractory depression receiving T had greater improvements in Hamilton Depression score than those on placebo (Pope 2003).
18Testosterone Effects on Physical Function and Mobility
19Change in Fat Free Mass (Kg) Effects of A Supraphysiologic Dose of Testosterone on Fat–Free Mass in Healthy Men6 -4 -2 -0 -Placebo Testosterone Placebo TestosteroneNo Exercise ExerciseChange in Fat Free Mass (Kg)0.8± ± ± ±0.6Bhasin S, Storer TW, et al, N Engl J Med 199619
20Evidence of Testosterone’s Anabolic Effects T replacement of hypogonadal men increasesFFM (2.3 kg, CI 1.2, 4.0)muscle size, andmuscle strength (Bhasin 1997; Wang 2000; Snyder 2000)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, andsome domains of HRQOL (Bhasin 1998, 2000; Grinspoon 1998, 2000)
21Meta-analysis Plot of Lean Body Mass Change in Older Men T increases muscle massMean Difference in LBM (kg) Change between Placebo and T GroupsBhasin Nature CPEM 2005
22T Dose Response in Young and Older Men: Change in Fat Free Mass T Dose Effect P <0.0001Age Effect P = 0.22Change in T X age P = 0.46Change inFFM (kg)T Dose (mg)Bhasin et al JCEM 2005
23T Dose Response in Young and Older Men: Change in Leg Press Strength T Dose Effect P = 0.008Age Effect 0.84Age X Change in serum T 0.29Change inLeg PressStrength (lb)T Dose (mg)Bhasin et al JCEM 2005
24T Effects on Physical Function Meta-analysis:No significant effect on overall SF-36 HRQOL scoreSignificantly greater improvement in physical function domain than placebo (0.5,95%CI 03, 0.9)Montori in: Bhasin et al, JCEM 2006 in pressSnyder et al JCEM 1999
25Possible Reasons for Failure to Demonstrate Consistent Improvements in Measures of Physical Function Inclusion of men who were not clearly hypogonadalT dose and conc. relatively lowStudies performed in healthy older men, not in frail or impaired menProblems with measurements of muscle performance and physical function:Are older men relatively insensitive to the anabolic effects of androgens?
26Testosterone Supplementation: Long-term Monitoring Concerns ErythrocytosisProstate cancer and exacerbation of BPHCardiovascular diseaseFluid retentionGynecomastiaSleep apneaWhen a patient is started on T supplementation, treatment is generally for life. The physician's responsibility for his monitoring is also for life. The areas requiring special attention are:The prostate. Evidence indicates that T administration to hypogonadal men produces negligible to modest increases in prostate size and prostatic specific antigen. However patients with significant obstructive symptoms or with suspected or documented cancer of the prostate (or breast) constitute absolute contraindications for T administration.Lipid profile. Evidence is emerging supporting the concept that low levels of T are associated with potentially unfavorable changes in triglycerides and HDL-C and that such abnormalities can be corrected by restoring physiological levels of androgens. Therefore, careful follow-up of the lipid profile is advisable when supplementing androgens in patients with significant risk factors for cardiovascular disease.Sleep apnea may be exacerbated by T administration. The same applies to polycythemia. Therefore, T must be administered to these patients with caution.Reports of liver toxicity manifested by jaundice and alteration of liver function studies have been limited almost exclusively to the methylated forms of testosterone. The injectable and oral esters of T as well as the transdermal are largely free of this adverse effect. Nevertheless, yearly liver function tests following institution of androgen therapy are advisable.The effect of T supplementation on a patient’s mind and emotional state should also be evaluated.Morales A. Int J Impot Res. 2000;12(suppl):10. Abstract S11.Heaton JP et al. In: Male Sexual Function. Humana Press; 2001: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
27Testosterone Supplementation and Risk of Prostate Cancer: Issues Many older men have microscopic foci of prostate cancer; T might make these subclinical foci grow.Older men with low T levels may have prostate cancer (Morgentaler et al, 1996)PSA levels increase after T administration (Meikle et al, 1997; Behre et al, 1994; Cooper et al, 1994).Inherent bias towards detection of greater number of prostate events in T-treated men (Calof 2005)Androgen therapy is normally for life; monitoring, therefore, is a serious commitment for both physician and patient. Monitoring should occur quarterly for the first year—and yearly thereafter—if no adverse events are detected.In men with ED, positive changes should be evident within 3 months after onset of treatment. If no improvement has occurred, comorbidities should be investigated.Tremblay J, Morales A. Aging Male. 1998;1:Adapted from Bhasin S, J Androl.2001;22: Bhasin et al, J Androl 2003
28Meta-Analysis of Adverse Events in Testosterone Replacement Trials in Older Men Rate fortestosteroneRate for placeboOdds Ratio95% CIProstate cancer5/6432/4271.110.48, 2.58PSA>427/64314/4271.200.68, 2.12Biopsies21/6431/4271.930.86, 4.37Total prostate events (cancer, biopsies, PSA>4, increased IPSS score)56/64318/4271.801.08, 3.00Hct>50%35/6433.691.20, 3.28All cardiac events (A fib, MI, chest pain, CABG, CVA)15/6431.100.55, 2.21Death0/6430.790.31, 1.98*computed using the Clopper-Pearson method ; random effects model
29Testosterone and Cardiovascular Risk Testosterone levels are lower in men with CAD than in healthy controls (Alexanderson 1996)Physiologic T replacement has little or no effect on plasma HDLC in older men (Snyder et al, 1999; Tenover 2000; Sih et al, 1997)Testosteroneimproves 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)T supplementation induces increase in LV mass (Casaburi unpublished)
30Sophie’s ChoiceTrade-off between beneficial effects of testosterone and the uncertainty about their adverse effectsHypothesis:SARMs and signaling effectors downstream of AR would provide better risk : benefit ratio
31Mechanisms of Androgen Action: Targets for Drug Discovery
32Mechanisms of Androgen Action: Testosterone Induces Muscle Fiber Hypertrophy 2000*600 vs 25mg: P<.051500600 vs 50 mg: P<.05Change in Type IIFiber Area (mm2)600 vs 125 mg: P<.05300 vs 25 mg: P<.05*1000500P = 0.003*1800600 vs 25 mg: P<.05600 vs 125 mg: P<.051400300 vs 25 mg: P<.05Change in Type IFiber Area (mm2)*1000600200P = 0.003TE Dose mg/wkSinha-Hikim et al, AJP Endo Metab 2002
33Testosterone Increases Myonuclear and Satellite Cell Number Number / mm481216125 mg mg mgSatellite CellTestosterone Enanthate Dose Levels***P = 0.04P = 0.03SInha-Hikim et al, AJP 2003
35A Model for Androgen Action on the Muscle Pluripotent Stem CellsA Model for Androgen Action on the MusclePre-adipocyte progenitor cellMature AdipocyteMyoblastMyotubeSatellite cellFat cell lineageMuscle cell lineageMyoDMHCDesminPre-adipocyte+-Mesenchymal Stem CellsLPLPPARγC/EBPαBhasin et al, J Gerontol Med Sci 2003; Bhasin et al Nature CPEM 2005
37Alterations in Intramuscular Gene Expression Associated with T Administration in HIV-Infected Men with Weight LossPRKAA2, PRKWNK1:AMPK, insulin signalingDIPA: adipogenesis inhibitorRORA: nuclear hormoneReceptor: interactionwith MyoDNCOA3: hormone rec.coactivator, IGF signalinghistone acetyltransferase,interacts with p300/CBPSYNCRIP: p68 kinaseInsulin signalingIL6ST: gp130 cytokineReceptor / STATSHARP:androgen receptor, Notch signalingTCF8: suppresses IL2IGF1: Insulin-likegrowth factor 1Placebo TestoTNFSF10:TRAIL / ApoptosisNFAT5: transcriptionfactor, WNT signalingTCF4: beta-catenin bindingtranscription factor,Wnt signalingAR: androgen receptorSOS2: MAPKsignalingSOS1: MAPK signalingPlacebo TestoATRX: helicase,chromatin remodellingTNFAIP6:hyaluronan-binding,TNF inducibleTK2: mitochondrial dNTP kinasemuscle activityDMPK: dystrophia myotonicaprotein kinaseMADH5: SMAD5, TGFb signalingAPOBEC3C: RNA editingAffymetrix U133A 2.0 chipMontano et al 2006
38Anti-BJS-1 Antibody Blocks T Effects on Myogenic Differentiation T+Anti-BJS-1BJS-1T+BJS1-AbBJS-1T+Anti-BJS-1BJS-1Singh et al (unpublished)T+BSJ1-AbBJS-1
39Jasuja, Singh, Bhasin (unpublished) BJS-1 as an Example of T-Activated Target that Acts Downstream of AR, Promotes Muscle Mass and BMD, but Spares the ProstateFat-Free MassBone Mineral DensityBJS-1Jasuja, Singh, Bhasin (unpublished)
40SARM Discovery Based on Recognition of Conformational Change Concern about prostatic effects in older men a major hurdle to the use of androgens as anabolic drugsCurrent screening strategies are based on AR binding and transactivation assays and favor selection of partial agonists: a flawed strategyHypothesis: 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).
42Tryptophan 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.
43Jasuja and Bhasin unpublished A High Throughput Screening Strategy Based on Conformational Change and FRET for SARM DevelopmentJasuja and Bhasin unpublished
44ConclusionsTotal and free T levels decline with advancing age and are weakly associated with clinical outcomes.Strong evidence that T supplementation increases:skeletal muscle massmaximal voluntary strength and leg powerdecreases whole body and regional fat masslibidoWeak evidence thatT therapy improves physical function, mood, and erectile functionEffects of T on clinical outcomes in older men with specific clinical syndromes: unknownThe long term risks: unknown
45Institute of Medicine Expert Panel Report on the Future of Testosterone Research Short-term RCTs of no longer than 1-year durationOlder men with specific syndromes, attributable to androgen deficiency, and low T levelsReplacement doses of testosteroneAdequately powered to determine efficacy using clinically relevant outcomes, rather than surrogate endpointsConduct larger trials to determine safety only if efficacy has been demonstratedBlazer et al, 2003; Snyder 2004; Barrett-Connor and Bhasin 2004
46Mechanisms of Androgen Action Androgens modulate differentiation of mesenchymal multipotent stem cellsAndrogens regulate mesenchymal stem cell differentiation by promoting the association of AR with beta-catonin and activating TCF-4.SpeculationMechanism-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
49Jasuja and Bhasin unpublished Conceptual Framework and Feasibility of a High Throughput Screening Strategy for SARMsJasuja and Bhasin unpublished
50Lesson 3 for Drug Discovery 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
51Barriers for Regulatory Approval T increases muscle mass and strength in older men, but improvements in physical function and clinical outcomes not demonstrated in men with physical dysfunctionUncertaintiesHow to operationalize the concept of individuals at risk for physical dysfunction and disability?What outcomes should be used as measures of efficacy in clinical trials?
52Mechanisms of Androgen Action 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
53Lesson 2 for Drug Discovery: Wnt-Target Genes, such as BJS-1, are Attractive Candidates Wnt signaling pathway:a major determinant of mesenchymal stem cell differentiationβ-catenin at the crossroads of several signaling pathways: targets downstream would have greater specificityPharmacophores that activate Wnt signaling would promote myogenesis and inhibit adipogenesis.Pharmacophores such as BJS-1 that activate Wnt-target genes downstream of AR would selectively increase muscle mass without affecting the prostate.
54Testosterone Supplementation in Men with Refractory Depression Study Design: Placebo-controlled, randomized, single-center, trialPatients: 23 men with refractory depression on anti-depressant therapy, with serum T <350 ng/dL.Treatment: Placebo or 10 g T gel daily X 8-weeksResults: 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:
55Endocrine Society Expert Panel’s Guidelines for Monitoring During Androgen Therapy At baseline, at 3, 6, 12 months after starting T therapy, monitor hemoglobin, PSA, DRE, AUA symptom score, sleep apnea scoresObtain 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
56An Investigator’s Prayer Oh Great Spirit: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.Please, soften the hearts of the reviewers of our grants and manuscripts, and keep us funded!
57The US Endocrine Society Expert Panel’s Recommendations: 2005 Recommended against a general clinical policy of offering testosterone therapy to all older men with low testosterone levels. (1|).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|)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|).
58CHANGE IN 6-MINUTE WALKING DISTANCE IN 6 MONTHS TESTOSTERONE TRIALCHANGE IN 6-MINUTE WALKING DISTANCE IN 6 MONTHS*+Meters**p<.05 vs control;+ p<.05 RT+T vs RTTestosterone treatment improved 6-minute walking distance to a greater extent than placebo in older men approaching frailty.
59Evidence that Androgen Binding Induces Specific Conformational Change 2nd order derivative spectra follows the bears and lambert’s law; the DHT inducedperturbations in tyrosine and tryptophan residues can be calculated as below:ab
60Calof and Bhasin J Gerontol 2005 Inherent Bias Towards Overestimation of Prostate Events in Testosterone-Arms of Clinical TrialsProstate biopsies usually triggered by PSA increments in clinical trialsPSA increments are more likely in T-treated men than in placebo-treated men.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
61Are Older Men Less Sensitive to the Anabolic Effects of Androgens?
62T Regulates Many Domains of Sexual Function in Men 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 (Alexander 1997)Attentiveness to erotic stimulus (Alexander 1997)Frequency and duration of nocturnal erections (Cunningham 1990, Carami 1990)T does not affect response to VES (Davidson 1978; Kwan 1979)
63The 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
65Team Testosterone Clinical Research Team Director: Linda Woodhouse Research Coordinators:-Tina Davidson-Connie Dzekov-Jeannie Dzekov-Veronica Sanatana-Jeff CelzadaExercise Physiology LaboratoryDirector: Thomas W. StorerTech: Lynn MaglianoBody CompositionLinda WoodhouseThomas W. StorerHormone AssaysIndrani Sinha-HikimMag Que
68Dose-Selection: Trade-Off Between Adverse Effects and Beneficial Effects Very substantial skeletal muscle remodeling is possible in healthy, older men with androgen administration.Trade-off between the dose, anabolic effects and adverse eventsBest trade-off was achieved at 125 mg/week TE dose:Very low frequency of AEsSerum T levels in the high normal rangeAverage 4.2 kg increase in FFMAverage 28 kg gain leg press strengthSARMs that are preferentially anabolic but do not have the adverse effects of T would be useful in sarcopenia associated with aging and chronic illness.
70Role of 5-Alpha Reductase and Aromatase in Mediating Androgen Action on Muscle -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 lossAromatase-Aromatase KO mice have decreased muscle mass and increased fat mass (Fisher et al, 1998)
71T Dose-dependently Improves Overall Sexual Function Scores in Older Men Change in Overall Sexual FunctionTestosterone Dose (mg/week)Overall ANOVA P=0.003.Gray et al 2005 in press
72T Dose Response in Young and Older Men: Change in Hemoglobin T Dose Effect P <0.0001Age Effect P < 0.001Change inHemoglobin(g/L)T Dose (mg)
73Effect of T Replacement on LV and RV Mass in Men with COPD LEFT VENTRICULARMASSRIGHT VENTRICULARMASSExercise – + – + – + – +TE – – + + – – + +
74Change in Specific Tension No ExerciseExercisePlaceboTestosteronePlaceboTestosterone*†*†Percent Change from Baselineoverall ANOVA, p=0.001* p<0.001 vs Placebo, No Exercise† p<0.001 vs Testosterone, No Exercise
75Changes in Erectile Function Change in Waking ErectionsChange in Spontaneous ErectionsTestosterone Dose (mg/week)Testosterone Dose (mg/week)Overall ANOVA P=0.024Overall ANOVA P=0.380
76T Dose Response in Young and Older Men: Change in Plasma HDL Cholesterol (mg/dL)T Dose Effect P = 0.001Age Effect P = 0.67Change in T level X Age effect P = 0.86T Dose (mg)
77Mechanisms of Androgen Action: Testosterone Induces Muscle Fiber Hypertrophy 2000*600 vs 25mg: P<.051500600 vs 50 mg: P<.05Change in Type IIFiber Area (mm2)600 vs 125 mg: P<.05300 vs 25 mg: P<.05*1000500P = 0.003*1800600 vs 25 mg: P<.05600 vs 125 mg: P<.051400300 vs 25 mg: P<.05Change in Type IFiber Area (mm2)*1000600200P = 0.003TE Dose mg/wkSinha-Hikim et al, AJP Endo Metab 2002
78Sinha-Hikim et al, AJP Endo 2003 Changes in Myonuclear and Satellite Cell Number After Treatment with GnRH Agonist and Testosterone16*12MyonuclearNumber / mm8P = 0.04**48*P = 0.03Satellite CellNumber / mm4125 mg mg mgSinha-Hikim et al, AJP Endo 2003Testosterone Enanthate Dose Levels
80Stimulation of MyoD Expression in 10T1/2 cell by T and DHT is inhibited by Bicalutamide DHT (10nM)BlankT (30nM)controlDHT (10nM) + Bic (100nM)T (30nM) + Bic (300nM)400XImmunocytochemistry**30*20Pos Nuclei/Total Nuclei x 100C vs. DHT p<0.01C vs. T p<0.05DHT vs. DHT + Bic p<0.001T vs. T + Bic p<0.001Image Analysis######10Singh et al, 2003CDHTTDHT+ BicT + Bic
81Dose-Dependent Inhibition of Adipogenesis by Androgens in Mesenchymal Pluripotent Cells Fat cells /10 fieldsSingh et al, 2003
82DHT Inhibits the Expression of PPAR-gamma and C/EBP-alpha in C3H10T1/2 Cells : DHT (nM)PPAR- -52 kD42 kDC/EBP30 kDGAPDH -40 kDSingh et al, Endocrinology 2003
83A Dominant Negative TCF4 cDNA Construct Blocks Testosterone Effects on Myogenesis in Mesenchymal Pluripotent CellsMHC+ Myotubes/hpf
84Effect of T Supplementation on Bone Mineral Density in Older Men Study Duration T Dose ResultsTenover 3 years 150-mg TE/2 wks Incr spinal andfem BMDSnyder 3 years 6-mg scrotal ptach Incr. spinal BMDKenny 1 year Nongenital patch Incr. Femoral BMD
85Summary and Conclusions T supplementation in eugonadal men, older men and men with chronic diseases and low T levels increases:skeletal muscle massmaximal voluntary strength and leg powerdecreases whole body and regional fat massT effects on physical function and health-related outcomes (disability, falls, well-being, QOL): unknownUncertainties:The long term risks: unknownNo consensus on how to operationalize the concept of individuals at risk for disabilityDo women have different T dose response relationships?
86Mechanisms of Androgen Action 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.Androgens regulate mesenchymal stem cell commitment by activating Wnt signaling.SpeculationModels 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.SARMs hold great promise for treatment of sarcopenia associated with aging and chronic illness, and for fat accumulation syndromes.
87Adverse Events Associated with T Administration in Older Men: A Meta-Analysis Criteria for inclusion in the systemic review:Placebo-controlled, RCTMiddle-aged or older men (>45 years of age)Medically stable individuals free of specific diseases“Replacement” doses of testosterone or its estersNumber of studies included = 17Number of subjects in placebo group = 427Number of subjects in T group = 643
88Operationalizing the Concept of Individuals at Risk for Disability Fried’s multi-dimensional construct of frailty (2001)Predicts risk of falls, disability, and mortalityAffects only 7% of men and women >65Difficult to operationalize in clinical trialsIdentifies a group with high morbidity and mortalityGill: Battery of physical function measures (1998, 1999)Guralnik: lower extremity function (1994, 1995)Sarcopenia defined in terms of appendicular skeletal muscle mass (Melton 2000; Baumgartner 1998)
89Sarcopenia as an Excellent Biomarker of Aging Is predictive of clinical outcomes: falls, fractures, and disability (Melton 2001; Baumgartner 1998)In cross-species comparisons, sarcopenia is predictive of biological age and mortality (Herndon 2002; Guarente 2000)Responsive to anabolic interventions (Bhasin 2001; Snyder 1999; Tenover 1992, 2000; Roubenoff 2002)Can be measured precisely and accurately (Kim et al, 2002; Heymsfield 1998)Significant changes demonstrable over short durations
90What Outcomes Should be Measured in Clinical Trails of Anabolic Therapies? Measures of muscle mass (DEXA, D2O)Measures of muscle performanceMuscle strength, power, and fatigabilityMeasures of Physical FunctionHealth-related outcomesSense of well-beingEnergy/fatigueAffectivity balancePhysical activityDisability scale
91Summary and Conclusions Different androgen-responsive functions have different T dose-response relationshipsAnabolic effects of T are correlated with T dose and conc.Older men are NOT less sensitive to anabolic effects of T.Older men differ from young men in other aspects:Older men have higher serum T levels: decreased clearanceOlder men have higher frequency of Hct> 54%, edema, and prostate eventsOlder men had a greater increase in Hg/Hct
92Edema and CHF During Testosterone Administration Leg edema observed largely in older men receiving supraphysiological dosesOccurred within 1-4 weeks of starting treatmentWas associated with SOB in two men who developed leg edema; echocardiograms in these two men revealed normal ejection fractions and evidence of diastolic dysfunctionPre-existing heart disease?
93We have learned much, but much remains unknown… 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.Long term safety unknownUncertainty about how to operationalize the concept of individuals at risk for disabilityDo women have different dose-response relationships than men?
94We have learned much, but much remains unknown… MechanismsHow do androgens increase muscle mass?Are anabolic effects AR-mediated? Non-genomic effectsThe kinetics and thermodynamics of T:AR interactionThe role of 5-alpha reduction and aromatization
95Effects of Testosterone and Resistance Exercise on Lean Body Mass (DEXA) in HIV+ Men with Low T LevelsNo ExerciseExercise**Change in FFM (kg)PlaceboTestosteronePlacebo+ExerciseTestosterone+Exercise* p<0.005 vs zero changeBhasin et al, JAMA 2000
96Androgen Therapy: Contraindications Prostate cancerBreast cancerBPH with severe symptom score or bladder outlet obstructionErythrocytosis with hematocrit >52%Severe sleep apneaSevere (class IV) congestive heart failureOlder men are the most likely candidates for androgen therapy. The choice of testosterone preparation depends on several factors, including availability, cost, and tolerance.A clear indication implies that symptoms of ADAM are present. It should be remembered that androgen deficiency affects different organs/systems with variable degrees of severity. Biochemical confirmation of hypogonadism is desirable prior to onset of therapy.Prostate safety remains the primary concern with androgen therapy. The presence of prostate cancer must be ruled out prior to testosterone administration. Breast cancer is also a contraindication.The presence of severe bladder outlet obstruction (BOO) is an absolute contraindicate for testosterone supplementation; moderate obstructive symptoms are not.Tremblay J, Morales A. Aging Male. 1998;1:Morales A et al. Int J Impot Res. 1996;8:95-97.Adapted from Bhasin, S, J Androl 2001;22:718-31; Andropause Consensus Panel, 2001Tremblay J, Morales A. Aging Male. 1998;1:
97Issues in SARM Development Can androgen administration improve muscle performance and produce meaningful improvements in health-related outcomes?What patient populations provide the best opportunities for initial efficacy trials?Uncertainty about measures of muscle performance and physical function that can be used as outcome measures in efficacy trialsLack of good correlation between Kd and in vivo potencyBetter measures of hormone:receptor interactionLack of good in vitro bioassays that are predictors of in vivo anabolic efficacyLack of good animal models of sarcopenia that can be used to demonstrate beneficial effects of SARMs
98T Dose Response in Young and Older Men: Change in Young’s Mania Rating Score T Dose (mg)
99Are Older Men Relatively Insensitive to Androgen Effects? Many changes during the aging process such as decreased sexual function, osteoporosis, and muscle loss are similar to those associated with androgen deficiency.Total and free T conc. in older men are lower than younger men, but most healthy older men have serum T in eugonadal range.
100Hypotheses-2Older men are not insensitive to the anabolic effects of T on lean body mass, muscle size and strength.
101Compliance with Study Treatment Young Men:Only one man in 126 mg dose missed one TE injectionGnRH agonist: 100%Older MenTE: 100%
102Study Design Sample Size: 11-13 men in each of the 5 treatment groups Treatment Duration: 20 weeksExercise stimulus was controlled.Protein and energy intake35 Kcal/kg/day, 1.5 g protein/kg/dayCompliance verified by 3-day food records and 24-hr phone recall
103T Dose Response in Young and Older Men: Change in Sexual Activity & Desire ScoresT Dose Effect P = NSAge Effect P = NST Dose (mg)
104T Dose Response in Young and Older Men: Change in PSA (ng/ml)T Dose Effect P = 0.58Age Effect P = 0.65Change in T level X Age Effect P = 0.13T Dose (mg)
105Testosterone Effects on HRQOL: Rationale Lean body mass is an important determinant of HRQOL in HIV-infected individuals (Wilson et al, 1999)Testosterone improves LBM and HRQOL in HIV-infected men (Grinspoon et al, 1998)Aging-associated impairment of physical function is associated with significant decrease in overall HRQOL (Wier et al).TRT improves rehabilitation outcomes in ill, older men (Bakhshi et al, 2000).
106T Dose Response in Young and Older Men: Change in Free T T dose effect, P<0.0001Age effect, P<0.0001Change in Free T (pg/mL)2550125300600TE (mg)
107Prevalent Dogma: Protein Synthesis as the Target of Androgen Action This hypothesis does NOT explain:The reciprocal decrease in fat massThe observed increase in myonuclear and satellite cell numberAR localization localization in precursor cells mostly outside the muscle fiberPluripotent Stem Cell Differentiation as the Target of Androgen Action: An Alternative HypothesisBhasin et al, J Gerontol 2003
108Effect of Age in Men on Body Fat, Lean Body Mass, and Weight 8070605040302010Age (years)Body Composition Component (kg)Forbes GB, Reina JC, Metab 1970;19:653
109Androgen Receptor is Expressed in Satellite Cells CD34ARCD34+ARAR Immunostaining
110Androgens Upregulate MyoD and MHC Expression *****mRNA*Myo D mRNA by Real-Time PCRMHCII Protein by WesternT (nM)-Az215 kDaMHCIIGAPDH-40 kDa
111Forest Plot of Mean Difference for Fat Mass Change -4.0-2.00.02.04.0Mean DifferenceStudyGrinsp 2000Bhasin 1998Storer 2004Grinsp 1998Grunfeld 2004Bhasin 2000CombinedSymbolIndividual
116Testosterone Effects on HRQOL: Rationale Lean body mass is an important determinant of HRQOL in HIV-infected individuals (Wilson et al, 1999)Testosterone improves LBM and HRQOL in HIV-infected men (Grinspoon et al, 1998)Aging-associated impairment of physical function is associated with significant decrease in overall HRQOL (Wier et al).TRT improves rehabilitation outcomes in ill, older men (Bakhshi et al, 2000).
117Effects of Testosterone Replacement in Older Men with Low or Low Normal T StudySubjectsTreatment Regimen in Body Comp in Muscle FunctionCommentsTenover, et al199260-75 y/oT<400 ng/dLTE 100 mg/wk for 3 months1.8 kg in FFMNo in FMNo in grip strengthMild in PSA and HCTMorley, et al199369-89 y/oBT<75 ng/dLTE 200 mg/2 wks for 3 monthsNo in FM or body weight in grip strength-Sih, et al1997Healthy, y/oBT<60 ng/dLTC 200 mg/2 wks for 12 monthsNo in body comp4-5 kg in grip strengthNo in PSA in HCT
118Effects of Testosterone Replacement in Older Men (cont) StudySubjectsTreatment Regimen in Body Comp in Muscle FunctionCommentsUrban, et al1995Healthy, >65 y/oT <480 nd/dLTE weekly for 4 wks to T to ng/dLBody comp not reported hamstring & quadriceps strength2-fold in muscle protein synth. rateSnyder, et al1999Healthy, >65 y/oScrotal T patch 6 mg/day for 3 yrs LBM kgFM 3 kgNo in knee extension & flexionImproved perception of physical functionTenover2000Healthy, older menTE 150 mg/2 wksfor 3 yrs FFM FMImproved grip strength-
119T and DHT induce nuclear translocation of -catenin Control40xDHT 10nMT 100nMDHT 10nM+BIC 100nMBIC 100nMRed: -catenin (Texas Red)Blue: counterstain (DAPI)
120Effects of Testosterone Replacement in Older Men (cont) Urban et al 2002Older men with T<17 nmol/LTE variable doseIncr. FFMIncr. muscle strengthIncr. IGF-1 and AR expressionKenny et al, 200177 older men bioT <4.4 nmol/LT patch 5 mg/d or placebo+1 kg Incr. In FFM, 2% decr. in FMIncr. In muscle strengthIncr. BMD
121Study Design GnRH TE Expected Group Agonist Dose T conc. I + 25 mg 175 ng/dLII + 50 mg 350 ng/dLIII mg 800 ng/dLIV mg 1400 ng/dLV mg 2500 ng/dL
122Summary of Adverse Events Numerically, greater number of adverse events and SAEs in older men than younger men: not statistically significant.None of the younger men had a SAE.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
123Dose-Selection: Trade-Off Between Adverse Effects and Beneficial Effects Higher the dose, greater the anabolic effects, and higher the frequency of adverse eventsBest trade-off was achieved at 125 mg/week TE dose; this dose was associated with:Very low frequency of AEsSerum T levels in the high normal rangeAverage 4.2 kg increase in FFMAverage 28 kg gain leg press strength
124Role of Testosterone in Spontaneous vs Induced Sexual Response Compared to eugonadal men, hypogonadal men had:Lower self-reported sexual activity, feelings and thoughtsLesser number of spontaneous erectionsSimilar erectile response to visual erotic stimulusTestosterone replacement for hypogonadal men:Increased sexual feelings and thoughts, and sexual activityIncreased number of spontaneous erectionsBut did not change erectile response to visual erotic stimulusSpontaneous, but not stimulus-induced, erectionsare testosterone dependentTestosterone stimulates sexual thoughts and feelingsKwan et al, J Clin Endocrinol Metab 1983;57:557-62
125Forest Plot of Mean Difference for FFM Change -6.0-2.51.04.58.0Mean DifferenceStudyBhasin 1998Storer 2004Bhasin 2000Grinsp 1998CombinedSymbolIndividual
126Mechanisms of Anabolic Effects on the Skeletal Muscle The increase in muscle strength is proportional to the increase in muscle mass; specific tension does not change (Storer 2004)T supplementation is associated with dose-dependent increase in hypertrophy of both type I and II fibers (Sinha-Hikim 2002).T-induced muscle hypertrophy is accompanied by an increase in the number of myonuclei and satellite cells (Sinha-Hikim 2003)
127T Supplementation in Older Men: The Issue of Our Times T prescription sales in the USA in 2004 >600 million dollars; 26-fold increase since 1993>1000 T-related stories in the media
128Change in Total T in Young and Older Men Treated with GnRH-A + TE T dose effect, P<0.0001Age effect, P<0.0001Change in T (ng/dL)2550125300600TE (mg)
129T Dose Response in Young and Older Men: Change in Fat Mass (DEXA) (kg)T Dose Effect P <0.0001Age effect P<0.001T Dose (mg)
130Age-Related Decline in Lean Mass and Muscle Strength (BLSA; Roy et al 2002) Quadricepes and Biceps Strength (N)Leg and Arm Lean Mass (kg)Age (years)Age (years)
131Powerful Demographic Trend Towards Aging of Human Populations Physical dysfunctionIncreased health care $$$$$$Sexual dysfunctionPoor HRQOLGrowing populations of older men and women around the globeCognitive impairment
133Testosterone and Cognition: Intervention Studies Study Intervention Patients ResultsAlexander T replacement hypogonadal Incr. verbal men fluencyVan Goozen T replacement Trans-sexual Incr.Spatial cognitionJanowsky T replacement Healthy older Incr. spatial men cognitionJanowsky T replacement Healthy older Improvedmen working memoryCherrier T replacement Older men Improved verbal memory and fluency
134Testosterone Effects on Mood Clinical Experience:Hypogonadal men report marked improvement in sense of wellbeing, energy, and mood after initiation of T therapyT therapy improves positive aspects of mood and decreases negative aspects of mood in hypogonadal men (Wang et al, JCEM 1996)No RCTs in older men
135Total Serum T Levels in Young and Older Men Treated with GnRH-A + TE T dose effect, P<0.0001Age effect, P<0.0001Serum T (ng/dL)2550125300600Bhasin et al JCEM 2005TE (mg)
136T Effects on Bone Outcomes No data on bone fracturesTwo trials of 3-years duration showed a moderate effect on lumbar bone density (0.4, CI 0.1,0.7) (Snyder 1999; Amory 2004)Ruled out a moderate treatment effect on femoral neck bone density (0.0, CI -0.3, 0.3)Montori 2005
137Rationale for T Supplementation in Older Men: Hypotheses T levels decline with advancing age.Low T associated with adverse health outcomesT supplementation improves physical, sexual, cognitive function, QOL and other health-related outcomesTestosterone administration is SAFE.
138Epidemiological Data: Weak Association of Low T and Outcomes Directly associated with:Muscle mass (Baumgartner 1998; Melton 2000),Strength of knee extension (Morley 2000)Self-reported physical function (MMAS 2005)Sexual desire (Beutel 2005)BMD, vBMD and bone geometry (Khosla 2005)Inversely associated with:CAD (Wu 2003; von Eckardstein 2003)Visceral fat (Seidell et al)Mortality (Shores et al 2006)
139Inconsistent or No Association Aging-related symptoms (T’Sjoen 2004)Prostate volume or LUTS (Schatzl 2000)Erectile Dysfunction (Korenman, 1996 ; Morley 1997)Depression indices (Seidman 2001; Barrett-Connor 2001; Schatzl 2000)
140Effects of T Therapy on Erectile Function and Libido Bolona et al. (unpublished)
141Sexual Function: A Complex, Multi-Component System
142Effects of Castration on Life Span and Cardiovascular Mortality Studies of “castrati” singersNieschlag (1993): no difference in life span between 50 castrated and 50 intact opera singersJenkins (1998): no difference between life span of 25 castrated and 25 intact singersStudies 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)Models of life span extension have low levels of sex hormones and growth factors (Bartke et al, 2002)
143Testosterone Increases Attentiveness to Erotic Stimuli 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?Testosterone Increases Attentiveness to Erotic StimuliTestosterone replacement therapy in hypogonadal men increases:Attentiveness to sexual stimulus in dichotic listening/selective attention taskAlexander et al, Horm Behav 1997;31:110-9.
144Testosterone Effects on Cognition Question: To determine effects of T on cognitive abilities in healthy older menDesign: Placebo-controlled, double-blind, randomized.Groups: TE 100 mg weekly vs. placebo X 6-wksResults: improvements with TRT inspatial 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
145T Dose Response in Young and Older Men: Change in Hamilton Depression Rating ScoreAge effect = NSDose Effect = NST Dose (mg)
146Meta-analysis Plot of Fat Mass Change in Older Men T deceases fat massBhasin Nature CPEM 2005Mean Difference in Fat Mass (kg) Change between Placebo and T Groups
147TESTOSTERONE TRIAL EFFECTS OF TESTOSTERONE ON PHYSICAL FUNCTION IN OLDER MEN (Page, S. T. et al. J Clin Endocrinol Metab 2005;90: )