Are Men Losing Their Gonads?

Are Men Losing Their Gonads? Andre B. Araujo, Ph.D. Director, Epidemiology New England Research Institutes Watertown, MA 02472 USA aaraujo@neriscience.com NIA R01AG020727 Endocrine Society Annual Meeting 2009 Washington, DC

Nothing to disclose Disclosure

Objectives/Outline What can population epidemiology do for endocrinology? Are men losing their gonads? Does it matter? Summary/Key questions

Objectives/Outline What can population epidemiology do for endocrinology? Are men losing their gonads? Does it matter? Summary/Key questions

What Is Epidemiology? Study of the distribution and determinants of disease in well-defined populations Distribution: prevalence, incidence Determinants: time, place, individual characteristics Well-defined population: WHO you study may determine WHAT you find Etiologic hypotheses (RCT) Disease control measures Lilienfeld J Chronic Dis 1960;11:471-483

The Illness Iceberg Clinical Studies Symptoms Recognized, Presented, Diagnosed, and Treated Population Studies Symptoms Not Recognized, Not Presented, or Not Diagnosed Last Lancet 1963;282:28-31

Studying the Whole Iceberg Distribution of disease How many cases in general population? How many being treated? What is normal range of laboratory test? Disease determinants Declines in T in association with age or comorbidity Associations not biased by selection factors

Epidemiology of Endocrine Function at NERI Massachusetts Male Aging Study (MMAS) Boston Area Community Health (BACH) Survey BACH/Bone Survey Intra-Subject Hormone Variation (ISHV) Study Registry of Hypogonadism in Men (RHYME) MMAS: O Donnell et al., Exp Gerontol 2004;39:975-984 BACH: McKinlay et al., Eur Urol 2007;52:389-396 BACH/Bone: Araujo et al., Osteoporos Int 2007;18:943-953 ISHV: Brambilla et al., Clin Endocrinol (Oxf) 2007;67:853-362

Objectives/Outline What can population epidemiology do for endocrinology? Are men losing their gonads? Does it matter? Summary/Key questions

T Declines with Age in Studies Worldwide FAMAS: Atlantis et al., Clin Endocrinol, e-pub ahead of print EMAS: Wu et al., J Clin Endocrinol Metab 2008;93:2737-2745 MMAS: Feldman et al., J Clin Endocrinol Metab 2002; 87:589-598 MrOS: Orwoll et al., J Clin Endocrinol Metab 2006;91:1336-1344 SAMS: Goh et al., Asian J Androl 2007;9:611-621

T Declines with Age in Studies Worldwide FAMAS: Atlantis et al., Clin Endocrinol, e-pub ahead of print EMAS: Wu et al., J Clin Endocrinol Metab 2008;93:2737-2745 MMAS: Feldman et al., J Clin Endocrinol Metab 2002; 87:589-598 MrOS: Orwoll et al., J Clin Endocrinol Metab 2006;91:1336-1344 SAMS: Goh et al., Asian J Androl 2007;9:611-621

EMAS: Cross-Sectional Age Trends Weak decline TT (-0.4%/y) Strong decline FT (-1.3%/y) Increasing LH Suggests a primary testicular defect I.e., men ARE losing their gonads as they age Wu et al., J Clin Endocrinol Metab 2008;93(7):2737 2745

MMAS: Longitudinal Age Trends Decrease Increase Weak decline TT (-1.6%/y) Strong decline FT (-2.6%/y) Increasing LH (+0.9%/y) Suggests decreased testicular response to increasing LH Feldman et al., J Clin Endocrinol Metab 2002;87(2):589 598

EMAS: Influence of Obesity Obesity ( ) Lower TT & FT independent of decreased SHBG LH lower in older obese men despite low T Suggests hypothalamic/ pituitary dysfunction I.e., Obese men ARE NOT losing their gonads Wu et al., J Clin Endocrinol Metab 2008;93(7):2737 2745

Population average decline in endocrine function However, all men not aging equally

MMAS: Individual Variation in Age Trend 1200 1000 800 600 Total T (ng/dl) 400 200 100 40 50 60 70 80 85 Age (y) Travison et al., J Clin Endocrinol Metab 2007;92:549-555

MMAS: Factors Associated with T Decline Adjusted age trend -10% per 10 y Covariate Predictor Total Testosterone Decline 95 % Confidence Interval Percent difference p- value Age and Aging Cross-sectional (10 y) -1.0 (-2.9, 1.0).33 Longitudinal (10 y) -10.1 (-12.5, -7.9) <.001 Health Diabetes -4.9 (-9.8, 0.1).05 Hypertension -4.7 (-7.7, -1.6).002 Medications 1-2 -1.5 (-4.3, 1.4).31 3-5 -1.8 (-5.4, 1.9).34 6+ -6.0 (-12.1, -1.0).03 Lifestyle Cigarette smoking 8.6 (5.2, 11.9) <.001 BMI (kg/m 2 ) -1.9 (-2.2, -1.6) <.001 Employment 3.2 (0.3, 6.5).04 Widowed -11.1 (-17.3, -4.6) <.001 Travison et al., J Clin Endocrinol Metab 2007;92:549-555

MMAS: Factors Associated with T Decline Adjusted age trend -10% per 10 y Health and lifestyle Significant effects on T decline when aging effects controlled Covariate Predictor Total Testosterone Decline 95 % Confidence Interval Percent difference p- value Age and Aging Cross-sectional (10 y) -1.0 (-2.9, 1.0).33 Longitudinal (10 y) -10.1 (-12.5, -7.9) <.001 Health Diabetes -4.9 (-9.8, 0.1).05 Hypertension -4.7 (-7.7, -1.6).002 Medications 1-2 -1.5 (-4.3, 1.4).31 3-5 -1.8 (-5.4, 1.9).34 6+ -6.0 (-12.1, -1.0).03 Lifestyle Cigarette smoking 8.6 (5.2, 11.9) <.001 BMI (kg/m 2 ) -1.9 (-2.2, -1.6) <.001 Employment 3.2 (0.3, 6.5).04 Widowed -11.1 (-17.3, -4.6) <.001 Travison et al., J Clin Endocrinol Metab 2007;92:549-555

MMAS: Factors Associated with T Decline Adjusted age trend -10% per 10 y Health and lifestyle Significant effects on T decline when aging effects controlled Magnitude of effects are substantial Diabetes + Htn ~ 10 y aging BMI 1 pt (7 lbs) ~ 2 y aging Covariate Predictor Total Testosterone Decline 95 % Confidence Interval Percent difference p- value Age and Aging Cross-sectional (10 y) -1.0 (-2.9, 1.0).33 Longitudinal (10 y) -10.1 (-12.5, -7.9) <.001 Health Diabetes -4.9 (-9.8, 0.1).05 Hypertension -4.7 (-7.7, -1.6).002 Medications 1-2 -1.5 (-4.3, 1.4).31 3-5 -1.8 (-5.4, 1.9).34 6+ -6.0 (-12.1, -1.0).03 Lifestyle Cigarette smoking 8.6 (5.2, 11.9) <.001 BMI (kg/m 2 ) -1.9 (-2.2, -1.6) <.001 Employment 3.2 (0.3, 6.5).04 Widowed -11.1 (-17.3, -4.6) <.001 Travison et al., J Clin Endocrinol Metab 2007;92:549-555

Age, health, and lifestyle important in T decline But not complete story

Age-Independent Population Decline in T Travison et al., J Clin Endocrinol Metab 2007;92:196-202

Age Trends by Birth Cohort Total Testosterone (ng/dl) 1200 1000 800 600 400 200 Age 65, born 1922, observed 1987: 500 ng/dl 1935-39 1940-45 1930-34 Age 65, born 1932, observed 1997: 444 ng/dl 1916-19 1920-24 1925-29 Age-matched time difference: -1.2%/y Potential explanations: Increases in BMI Increases in Rx Decreases in smoking Unmeasured health/ environmental factors 100 45 50 55 60 65 70 75 80 Age (y) Travison et al., J Clin Endocrinol Metab 2007;92:196-202

Replication: Age-Independent Decline MONICA and Inter99 studies (Denmark) Lower T and SHBG levels observed in men born more recently Secular decrease in SHBG independent of BMI Andersson et al., J Clin Endocrinol Metab 2007;92:4696-4705

Interim Summary Age trends TT declines weakly FT declines strongly LH increases Parallel T trends with time à Aging men losing their gonads (primary testicular failure) Obesity Decreased T No change in LH à Obese aging men not losing their gonads (hypothalamic/pituitary origin)

Objectives/Outline What can population epidemiology do for endocrinology? Are men losing their gonads? Does it matter? Summary/Key questions

Markers of Fall Risk

In Men without Mobility Limitations on Lupron, IM T Therapy Increases Muscle Mass and Maximal Voluntary Strength Storer et al., J Am Geriatr Soc 2008;56:1991-1999

But Not Physical Function Storer et al., J Am Geriatr Soc 2008;56:1991-1999

In Sedentary Men with Low T, T or T+F Increases Physical Function Page J Clin Endocrinol Metab 2005;90:1502-1510

WHO you study may determine WHAT you find

Markers of Bone Strength

High Prevalence of Low T (<200 ng/dl) in Osteoporosis 8.0% 7.0% 6.9% Percent with T < 200 ng/dl 6.0% 5.0% 4.0% 3.0% 2.0% 3.2% 2.4% 1.0% 0.0% Normal Osteopenic Osteoporotic Hip Osteoporosis Category Fink et al., J Clin Endocrinol Metab 2006;91:3908-3915

IM T Therapy Improves Lumbar Spine BMD Tracz et al., J Clin Endocrinol Metab 2006:91(6):2011 2016

Reduced Trabecular Architecture in Men with HG vs. Normal Benito et al., J Clin Endocrinol Metab 2003;88:1497-1502

T and Trabecular Architecture in Normal Men Population study of 269 men 21-97 y Trabecular architecture assessed by HR-pQCT Association between Bio-T and trabecular thickness/separation emerges with age Khosla et al., J Clin Endocrinol Metab 2006;91:885 891

WHO you study may determine WHAT you find

Low T Increases Fracture Risk Meier et al., Arch Intern Med 2008;168(1):47-54

Diabetes

In Prospective Studies, T Appears to Lower Risk of Diabetes Ding et al., J Am Med Assoc 2006;295:1288-1299

Ding et al., J Am Med Assoc 2006;295:1288-1299 As Does SHBG

T, SHBG, and Diabetes T bound tightly to SHBG Are their influences independent? Is T influence due to an androgenic influence? a non-androgenic influence mediated by SHBG?

MMAS: Relative Influence of Decreased T and SHBG on Diabetes Hazard Ratio (95% CI) Hormone SD Model 1 Model 2 Total T 172.1 ng/dl 1.29 (1.01-1.66) 1.05 (0.80-1.38) SHBG 15.7 nmol/l 2.00 (1.42-2.82) 1.95 (1.34-2.82) Model 1: Total T or SHBG alone plus age, BMI, high blood pressure, smoking, alcohol intake and physical activity SHBG and T both predict diabetes incidence in multivariate models Model 2: Total T and SHBG plus age, BMI, high blood pressure, smoking, alcohol intake and physical activity SHBG confounds T influence Lakshman et al., Unpublished MMAS data

Mortality

T and Mortality Author Study N Mean Age Mortality Follow-up ~Percentage mortality per year Low T Finding WRT Death Smith et al., 2005 Caerphilly 2,512 52 y 19% 17 y 1.1%/y No effect Araujo et al., 2007 MMAS 1,686 55 y 23% 15 y 1.5%/y No effect Tivesten et al., 2009 Lehtonen et al., 2008 MrOS Sweden Turku, Finland 3,014 75 y 12.7% 4.5 y 2.8%/y Increased risk 187 71 y 36% 10 y 3.6%/y Increased risk Maggio et al., 2007 InChianti 410 ~75 y 31% 6 y 5%/y No effect Shores et al., 2006 UW VA 858 61 y 24% 4 y 6%/y Increased risk Laughlin et al., 2007 Jankowska et al., 2009 Shores et al., 2004 Rancho- Bernardo 2 tertiary reference cardiology centers, HF patients UW VA Rehab Unit 794 71 y 68% 12 y 6%/y Increased risk 501 58 y 34% 3 y 11.0%/y Increased risk 44 ~75 y 23% 6 mo 45%/y Increased risk Khaw et al., 2007 Epic- Norfolk 2,314 ~68 y Fixed (casecontrol study) 10 y NA Increased risk

T and Mortality Author Study N Mean Age Mortality Follow-up ~Percentage mortality per year Low T Finding WRT Death Smith et al., 2005 Caerphilly 2,512 52 y 19% 17 y 1.1%/y No effect Araujo et al., 2007 MMAS 1,686 55 y 23% 15 y 1.5%/y No effect Tivesten et al., 2009 Lehtonen et al., 2008 MrOS Sweden Turku, Finland 3,014 75 y 12.7% 4.5 y 2.8%/y Increased risk 187 71 y 36% 10 y 3.6%/y Increased risk Maggio et al., 2007 InChianti 410 ~75 y 31% 6 y 5%/y No effect Shores et al., 2006 UW VA 858 61 y 24% 4 y 6%/y Increased risk Laughlin et al., 2007 Jankowska et al., 2009 Shores et al., 2004 Rancho- Bernardo 2 tertiary reference cardiology centers, HF patients UW VA Rehab Unit 794 71 y 68% 12 y 6%/y Increased risk 501 58 y 34% 3 y 11.0%/y Increased risk 44 ~75 y 23% 6 mo 45%/y Increased risk Khaw et al., 2007 Epic- Norfolk 2,314 ~68 y Fixed (casecontrol study) 10 y NA Increased risk

T and Mortality Author Study N Mean Age Mortality Follow-up ~Percentage mortality per year Low T Finding WRT Death Smith et al., 2005 Caerphilly 2,512 52 y 19% 17 y 1.1%/y No effect Araujo et al., 2007 MMAS 1,686 55 y 23% 15 y 1.5%/y No effect Tivesten et al., 2009 Lehtonen et al., 2008 MrOS Sweden Turku, Finland 3,014 75 y 12.7% 4.5 y 2.8%/y Increased risk 187 71 y 36% 10 y 3.6%/y Increased risk Maggio et al., 2007 InChianti 410 ~75 y 31% 6 y 5%/y No effect Shores et al., 2006 UW VA 858 61 y 24% 4 y 6%/y Increased risk Laughlin et al., 2007 Jankowska et al., 2009 Shores et al., 2004 Rancho- Bernardo 2 tertiary reference cardiology centers, HF patients UW VA Rehab Unit 794 71 y 68% 12 y 6%/y Increased risk 501 58 y 34% 3 y 11.0%/y Increased risk 44 ~75 y 23% 6 mo 45%/y Increased risk Khaw et al., 2007 Epic- Norfolk 2,314 ~68 y Fixed (casecontrol study) 10 y NA Increased risk

WHO you study may determine WHAT you find!

Objectives/Outline What can population epidemiology do for endocrinology? Are men losing their gonads? Does it matter? Summary/Key questions

Population studies Summary Fundamental to endocrinology T declines in most, but not all, men As they age and with time Men appear to be losing their gonads with age, but not obesity Not all due to aging, and can be modified by health/lifestyle Low T has significant impact on health

Key Questions for Population Epidemiology Secular decline in T Is it real? If so, what are the mechanisms? Low T and obesity Why no decreased testicular response with aging? Are clinical outcomes in age- or obesity-related T declines similar or different? How important is T vis-à-vis SHBG? Can T decline be prevented?

Acknowledgements R01AG020727