ADAM SyndromeADAM SyndromeAndrogen Deficiency in the Aging Androgen Deficiency in the Aging

ManManAndropauseAndropause

Norman Jensen MD MSNorman Jensen MD MSProfessor EmeritusProfessor Emeritus

UW Department of MedicineUW Department of Medicinenmj@medicine.wisc.edunmj@medicine.wisc.edu

Primary Care Conference, March 28, 2007Primary Care Conference, March 28, 2007

“Is it not strange that desire should so many years outlive performance?” Shakespeare, W: Henry IV Part2.

ILOsILOsIntended Learning OutcomesIntended Learning Outcomes

a.k.a., Learning Objectivesa.k.a., Learning Objectives

Androgen physiologyAndrogen physiology Androgen changes with agingAndrogen changes with aging Syndrome of ADAMSyndrome of ADAM Effects of testosterone Effects of testosterone

replacementreplacement Practice guidelinePractice guideline

Literature SearchLiterature Search MESH Major: Hypogonadism 5,914 OR MESH Major: Hypogonadism 5,914 OR

Testosterone 24,304 = 29,507Testosterone 24,304 = 29,507 Limits: Limits:

– Human, Male, English, Adult 19+ = 5,267 Human, Male, English, Adult 19+ = 5,267 – Last 10 years = 1930Last 10 years = 1930– Core clinical journals = 454Core clinical journals = 454– Randomized Clinical Trials = 115 Randomized Clinical Trials = 115 – Reviews = 25Reviews = 25– Meta-analysis = 1Meta-analysis = 1– Practice Guideline = 0Practice Guideline = 0– Total = 141Total = 141

Testis, gross anatomyTestis, gross anatomy

Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:479.

Normal testicular Normal testicular volumevolume

> 15 ml.

Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:486.

Testis, micro anatomyTestis, micro anatomy

Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:479.

Testis, Testis, photomicrographphotomicrograph

Hypothalamus – Pituitary – Testis Axis

Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:483.

Aromatase → E2

5α reductase → DHT

Androgen Androgen metabolismetabolis

mm

Finasteride & dutasteride

Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:481.

Licorice

DHEA = popular food supplement androgen

Normal androgen Normal androgen sourcessources

Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:482.

Normal androgen levels, Normal androgen levels, serum serum

Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:486.

Mechanism of Action, TMechanism of Action, T

LH and Testosterone Excretion - Diurnal Rhythms

Winters SJ. Diurnal rhythm of testosterone and LH in hypogonadal men. J Andrology 1991;12:185-190. (Pittsburgh)

Ovarian hormone Ovarian hormone lifetimelifetime

Testosterone in aging Testosterone in aging menmen

Prevalence of Low T by Prevalence of Low T by AgeAge

NEJM 2004;350:483

Clinical male Clinical male hypogonadismhypogonadism

NEJM 2004;350:483

USA USA Prevalence = Prevalence = 2-4 million2-4 million

~ 5% on Rx~ 5% on Rx

Etiology, male Etiology, male hypogonadismhypogonadism

Endocr Pract 2002;8:440-456

Benefits of Benefits of Testosterone replacementTestosterone replacement Sexual dysfunctionSexual dysfunction Bone density & Lean muscle massBone density & Lean muscle mass Strength, endurance, fallsStrength, endurance, falls Mood and cognitionMood and cognition ErythropoesisErythropoesis HIV-AIDSHIV-AIDS

sense of well-being and muscle masssense of well-being and muscle mass Anti-inflammatoryAnti-inflammatory Metabolic: Metabolic: insulin resistance, A1c, visceral insulin resistance, A1c, visceral

adiposity, total cholesterol, BP?, pre-diabetesadiposity, total cholesterol, BP?, pre-diabetes

Potential Harms of TPotential Harms of T

IoM concluded “no compelling IoM concluded “no compelling evidence of major adverse side evidence of major adverse side effects resulting from T therapy”.effects resulting from T therapy”.

““Prostate events”Prostate events”– BPH (BPH ( vol), LUTS, retention, CA vol), LUTS, retention, CA

Obstructive sleep apneaObstructive sleep apnea ErythrocytosisErythrocytosis

CardiovascularCardiovascular Benefits & HarmsBenefits & Harms

No clinical trial evidence of eitherNo clinical trial evidence of either However, lots of observational dataHowever, lots of observational data

Angiogram disease with lower TAngiogram disease with lower T• Top 1/3 serum T = 0.2 age-adjusted relative riskTop 1/3 serum T = 0.2 age-adjusted relative risk• Mid 1/3 serum T = 0.4Mid 1/3 serum T = 0.4

exercise-free angina for men on T (Heart 2004;90:871-exercise-free angina for men on T (Heart 2004;90:871-6)6)

coronary artery diameter when injected directly with Tcoronary artery diameter when injected directly with T Men on T have Men on T have antithrombin III offsetting antithrombin III offsetting

prothrombotic factors, prothrombinase, proteins C & S. prothrombotic factors, prothrombinase, proteins C & S. No effects on platelets.No effects on platelets. No No in Cardiovascular events in Cardiovascular events No effect or No effect or Tot cholesterol, LDL, HDL Tot cholesterol, LDL, HDL TNFTNFαα & IL1 & IL1ββ and and IL-10IL-10

Refs: Rhoden, NEJM 2004 / JCEM 2004;89:3313-18 / Heart2004;90:871-6.Refs: Rhoden, NEJM 2004 / JCEM 2004;89:3313-18 / Heart2004;90:871-6.

ErythropoesisErythropoesisBenefits & harmsBenefits & harms

Hgb Hgb 15-20 in boys at puberty 15-20 in boys at puberty Men have higher Hgb than womenMen have higher Hgb than women Hypogonad men have lower HgbHypogonad men have lower Hgb

Corrected by T replacement in 3 monthsCorrected by T replacement in 3 months

Risk of erythrocytosis (HCT > 52)Risk of erythrocytosis (HCT > 52) with pulmonary insufficiencywith pulmonary insufficiency– dose relateddose related

No case reports of thromboembolism No case reports of thromboembolism with Twith T

Monitor Hgb or HctMonitor Hgb or Hct

Prostate DiseaseProstate DiseaseRisks and BenefitsRisks and Benefits

No benefits observedNo benefits observed P volume with Rx during first 6 P volume with Rx during first 6

months; months; with castration with castration (surgical or (surgical or medical)medical)

Risks of T RxRisks of T Rx No No LUTS or retention LUTS or retention Castration causes P cancer regressionCastration causes P cancer regression No clinical trial evidence for No clinical trial evidence for growth growth Case reports onlyCase reports only P ca prevalent at age when T is decliningP ca prevalent at age when T is declining

Effects of T Effects of T ReplacementReplacement

J Clin Edocrinol Metab 2000;85:2670-77J Clin Edocrinol Metab 2000;85:2670-77• Case series: 18 men > 18 y/o, hypoT due to Case series: 18 men > 18 y/o, hypoT due to

organic disease (78+-77 ng/dl), never treated. Rx T organic disease (78+-77 ng/dl), never treated. Rx T transdermal 3 years. 16 completed 12 months, 14 transdermal 3 years. 16 completed 12 months, 14 all 36.all 36.

• Results: Serum T normalized. L2-4 BMD Results: Serum T normalized. L2-4 BMD 7.7%+- 7.7%+-7.6(.001), fem trochanter BMD 7.6(.001), fem trochanter BMD 4.0+--5.4%(.02) 4.0+--5.4%(.02) (both max 24 mos), lean body mass (both max 24 mos), lean body mass 3.1 kg (.004), 3.1 kg (.004), HCT HCT 38+-3% to 43.1+-4%(.002), prostate volume 38+-3% to 43.1+-4%(.002), prostate volume 12+-6 mL to 22.4+-8.4 mL (.004), energy 12+-6 mL to 22.4+-8.4 mL (.004), energy 49+- 49+-19%66+-24% (.01), and sexual function 19%66+-24% (.01), and sexual function 24+-20% 24+-20% to 66 +-24% (.001). Lipids did not change.to 66 +-24% (.001). Lipids did not change.

• Full effect on BMD took 24 mos, all others 3-6 mos.Full effect on BMD took 24 mos, all others 3-6 mos.

Bone mineralBone mineral J Clin Edocrinol Metab 2002;87:3656-61J Clin Edocrinol Metab 2002;87:3656-61

Case-control study: 15 men 75y/o PCA Case-control study: 15 men 75y/o PCA & 17 normals 70y/o& 17 normals 70y/o

12 months after GnRh analog rx12 months after GnRh analog rx(chemical (chemical

castration)castration):: Total hip Total hip 3.3%, distal radius 3.3%, distal radius 5.3% (.001) 5.3% (.001) Spine Spine 2.8% (ns), femoral neck 2.8% (ns), femoral neck 2.3% (ns) 2.3% (ns) urine N-telopeptide (<.05) urine N-telopeptide (<.05)

– (marker of bone resorption)(marker of bone resorption) No bone loss in controls.No bone loss in controls.

NEJM 2001;345:948-935 – bone loss with ADT prevented NEJM 2001;345:948-935 – bone loss with ADT prevented by pamidronate infusions. And alendronate by pamidronate infusions. And alendronate (Osteoporosis International 2005;16:1591-96)(Osteoporosis International 2005;16:1591-96)

Physical Physical functioningfunctioning J Clin Endocrinol Metab J Clin Endocrinol Metab

2005;90:1502-15102005;90:1502-1510 RCT: 70 T<350ng/dl, >64y/o to 200 mg / 2 RCT: 70 T<350ng/dl, >64y/o to 200 mg / 2 wks vs. placebo X 36 months, 50 wks vs. placebo X 36 months, 50 completedcompleted

Results: Results: – Significant Significant timed function test*, handgrip timed function test*, handgrip

strength (160%L & 900%R), & lean body mass, strength (160%L & 900%R), & lean body mass, fat mass 17%, total cholesterol 19% & LDL fat mass 17%, total cholesterol 19% & LDL

22%22%– NS trends in HDL -15% & fasting insulin -15%.NS trends in HDL -15% & fasting insulin -15%.

Physical Physical functioningfunctioning

European J Endocrinology European J Endocrinology 2006;155:867-75.2006;155:867-75. RCT: n=70, 5 mg testoderm, placebo, RCT: n=70, 5 mg testoderm, placebo,

exercise*, no exercise, 4 arms, 12 wks, 65-exercise*, no exercise, 4 arms, 12 wks, 65-85 for SF36 and dual x-ray absorptiometry 85 for SF36 and dual x-ray absorptiometry scan.scan.

Results: T + Ex, Results: T + Ex, physical function (.03), physical function (.03), role physical (.01), general health (.049), & role physical (.01), general health (.049), & social functioning (.04).social functioning (.04).

* home program, 11 resistive exercises, 10 * home program, 11 resistive exercises, 10 each / day, 3-4 d/wk, using elastic bands, of each / day, 3-4 d/wk, using elastic bands, of various strengths, followed q2wkvarious strengths, followed q2wk

Metabolic Syndrome Metabolic Syndrome

ObservationsObservations T and insulin levels inversely relatedT and insulin levels inversely related Low T predict ins. res. and future DNLow T predict ins. res. and future DN Men with DM more likely hypoT, ~33%Men with DM more likely hypoT, ~33% fT low in obese men, inversely :: BMIfT low in obese men, inversely :: BMI HyopT have HyopT have abdom obesity abdom obesity Obesity Obesity T via aromatase conversion to E2 and T via aromatase conversion to E2 and

via via leptin leptin Insulin Insulin after GnRH agonist after GnRH agonist Insulin & sugar levels Insulin & sugar levels after castration after castration HypoT associated with HBP, dyslipid, & Metabolic HypoT associated with HBP, dyslipid, & Metabolic

Syndrome regardless of BMISyndrome regardless of BMI

Metabolic Syndrome Metabolic Syndrome

Experimental studiesExperimental studies Castrated rats show impaired insulin Castrated rats show impaired insulin

sensitivity corrected with physiologic Tsensitivity corrected with physiologic T Healthy men with low T improved insulin Healthy men with low T improved insulin

sensitivity and sensitivity and insulin after T insulin after T replacementreplacement

T rx T rx insulin resistance in obese men insulin resistance in obese men T rx T rx TChol in hypoT men with CAD, even TChol in hypoT men with CAD, even

in those on statinsin those on statins A report of improved A1c on T rxA report of improved A1c on T rx

Metabolic SyndromeMetabolic SyndromeEuropean J Endocrinology, 2006;154:899-906European J Endocrinology, 2006;154:899-906

Study, RCT, xo 3-1-3, 27 men age>30, Study, RCT, xo 3-1-3, 27 men age>30, hypoT and DM2, T200mg IMq2wk.hypoT and DM2, T200mg IMq2wk.

Results: Results: Insulin 14% (ns), Insulin 14% (ns), FBS 6%(.03), FBS 6%(.03), A1c 4%[.3] A1c 4%[.3]

(.03)(.03)TChol 5%(.03), TChol 5%(.03), %body fat 3%(ns), %body fat 3%(ns), waist circumference (.03), waist circumference (.03), waist:hip (.01) waist:hip (.01)

– No change in BMI, HDL, LDL, Trig, SysBP, No change in BMI, HDL, LDL, Trig, SysBP, DiaBPDiaBP

Conclusion: T Conclusion: T insulin resistance & insulin resistance & glycemia in hypogonad men with DM2glycemia in hypogonad men with DM2

Men with DM2 & met. Syndrome should Men with DM2 & met. Syndrome should be evaluated for hypogonadism. be evaluated for hypogonadism. J Urol J Urol 2005;174:827-34 (review)2005;174:827-34 (review)

CognitionCognitionAging Male 2003;6:13-18.Aging Male 2003;6:13-18.

RCT (pilot): 10 men w new dx RCT (pilot): 10 men w new dx Alzheimer’s & hypoT (<240 ng/dl), 5 rx Alzheimer’s & hypoT (<240 ng/dl), 5 rx T 200 mg / 2wks & 5 placebo & tested T 200 mg / 2wks & 5 placebo & tested at 3, 6, 9, 12 months.at 3, 6, 9, 12 months.

RESULTS: MMSE RESULTS: MMSE 19.4 to 23.2 (.02) – 19.4 to 23.2 (.02) – comparable to ACH inhibitors. comparable to ACH inhibitors.

Clock draw test Clock draw test 2.2 to 3.2 (.07) 2.2 to 3.2 (.07) Animal studies: T enhances ACH Animal studies: T enhances ACH

release, release, nicotinic receptors, and nicotinic receptors, and affects Tau protein deposition.affects Tau protein deposition.

brain amyloid beta-peptide after GnRH brain amyloid beta-peptide after GnRH analogs (e.g. Lupron)analogs (e.g. Lupron)

Observed associations of T and memoryObserved associations of T and memory

Adverse Adverse EffectsEffects

ofofTestosteroTestostero

neneRxRx

NEJM 2004;350:485

Adverse Adverse EffectsEffects

ofofT RxT Rx

NEJM 2004;350:484

Risk of Prostate CancerRisk of Prostate Cancerqualitative reviewqualitative review

Calof OM, Singh AB, Martin LL, et.al. Calof OM, Singh AB, Martin LL, et.al. Adverse eventsAdverse events associated with testosterone replacement in middle-associated with testosterone replacement in middle-

aged and older men: A aged and older men: A meta-analysismeta-analysis of of randomized, placebo-controlled trials. randomized, placebo-controlled trials.

Journal of Gerontology 2005;11:1451-1457.Journal of Gerontology 2005;11:1451-1457. 1966 – 4/2004: Testosterone (MESH), limited 1966 – 4/2004: Testosterone (MESH), limited

by human, male, >44 y/o, RCT = 417+1, 19 of by human, male, >44 y/o, RCT = 417+1, 19 of which met inclusion criteria of T rx >90 days, which met inclusion criteria of T rx >90 days, initial low / low-normal T, medically stable.initial low / low-normal T, medically stable.

615 Rx’d with T, 433 placebo.615 Rx’d with T, 433 placebo. All 5 Prostate events OR = 1.78 (1.07-2.95)All 5 Prostate events OR = 1.78 (1.07-2.95)

– None individually significant, strongest trend = BxNone individually significant, strongest trend = Bx– Prostate cancer (PSA>4 & +Bx) OR 1.09 (0.49 – 2.49)Prostate cancer (PSA>4 & +Bx) OR 1.09 (0.49 – 2.49)

HCT > 50% OR 3.69 (1.82-7.51)HCT > 50% OR 3.69 (1.82-7.51) CV, OSA, death = not statistically different with trend CV, OSA, death = not statistically different with trend

for lower CV events (ex. Arrhythmia) and deathsfor lower CV events (ex. Arrhythmia) and deaths N = 85,862 to detect 20% N = 85,862 to detect 20% p CA for 1 year p CA for 1 year

– So IoM recommends short term efficacy trials as next So IoM recommends short term efficacy trials as next stepstep

MonitorinMonitoring g

GuidelineGuideline

NEJM 2004;350:488

? lipids

If the PSA risesIf the PSA rises

What to do until the What to do until the evidence is in?evidence is in?

Stringent diagnostic criteriaStringent diagnostic criteria 3 early AM total * T’s < 200 ng/dl3 early AM total * T’s < 200 ng/dl High LH = primary hypogonadismHigh LH = primary hypogonadism NL or low LH = secondary hypogonatismNL or low LH = secondary hypogonatism

– √ √ Serum TSH, fT4, cortisol, prolactin, & MRI brain/sellaSerum TSH, fT4, cortisol, prolactin, & MRI brain/sella Rx T only if above criteria met.Rx T only if above criteria met. If T Rx, monitor serum T & sxIf T Rx, monitor serum T & sx

Goal: ? young men’s normal 500-700 vs. Goal: ? young men’s normal 500-700 vs. Goal: ? older men’s normal 300-450 ng/dl (“prudent”)Goal: ? older men’s normal 300-450 ng/dl (“prudent”)

Screen & Monitor for adverse risk & Screen & Monitor for adverse risk & outcomesoutcomes

See previous slidesSee previous slides

NEJM 2004;350:482-492, 440-442, & 2004-2006.NEJM 2004;350:482-492, 440-442, & 2004-2006.

Rx: androgen (Class III Rx: androgen (Class III 1991)1991)

Testosterone cipionate, 200 mg/ml./2 wkTestosterone cipionate, 200 mg/ml./2 wk 200 mg/ml, 10 ml. vial, $88.99, = $ 18 / month * 200 mg/ml, 10 ml. vial, $88.99, = $ 18 / month * $65.42 /ml+$65.42 /ml+

Testosterone enanthate, 200 mg/ml/2wkTestosterone enanthate, 200 mg/ml/2wk * not listed* not listed $44.78 / ml+$44.78 / ml+

Testosterone topical, 5-10 gm / amTestosterone topical, 5-10 gm / am 1% gel, @ 5 gm / day = $ 210-230 / month *1% gel, @ 5 gm / day = $ 210-230 / month * Androgel and TestimAndrogel and Testim $227.75/ mo+$227.75/ mo+

Testosterone transdermal patchTestosterone transdermal patch 2.5 – 10 mg. qhs, @ 5 mg/d “Androderm”2.5 – 10 mg. qhs, @ 5 mg/d “Androderm” $223.03 / mo+$223.03 / mo+

””Testaderm”Testaderm”$112.29 / mo +$112.29 / mo +

Testosterone, oral, methyltestosterone & fluoxymesteroneTestosterone, oral, methyltestosterone & fluoxymesterone Erratic absorption, less effective, cholestasisErratic absorption, less effective, cholestasis 10-50 mg. po / day - @ 20 mg/d = $187 / month *10-50 mg. po / day - @ 20 mg/d = $187 / month * NANA

Testosterone buccal, 30 mg. q 12 hTestosterone buccal, 30 mg. q 12 h 30 mg., #60 = $222.42, = $ 220 / month * “Striant”30 mg., #60 = $222.42, = $ 220 / month * “Striant”

$213.20 / mo+$213.20 / mo+ Testosterone pellets, injected SQ, Testosterone pellets, injected SQ, NANA

75 mg/pellet, 3-6 / 3-6 mos., “Testopel” $160 + $20/pellet + visit75 mg/pellet, 3-6 / 3-6 mos., “Testopel” $160 + $20/pellet + visit 100 mg & 200 mg pellets compounded by some pharmacies100 mg & 200 mg pellets compounded by some pharmacies

* Epocrates, Drug Store.com prices * Epocrates, Drug Store.com prices + Price, UWH pharmacy+ Price, UWH pharmacy

Tests Available at UWHTests Available at UWH

Testosterone, TotalTestosterone, Total Testosterone Free, Adult Male * Testosterone Free, Adult Male * Testosterone, Bio-available and SeTestosterone, Bio-available and Se

x Hormone Binding Globulin, Adult x Hormone Binding Globulin, Adult MaleMale

5-a-Dihydrotestosterone5-a-Dihydrotestosterone

* ARUP uses RAI measurement adjusted by a complex formula * ARUP uses RAI measurement adjusted by a complex formula including measures of albumin and sex hormone binding globulin and including measures of albumin and sex hormone binding globulin and known binding constants. The R2 = 0.94 when compared to Endocrine known binding constants. The R2 = 0.94 when compared to Endocrine Science’s equilibrium dialysis method. The unreliable RAI test is a Science’s equilibrium dialysis method. The unreliable RAI test is a direct measurement, unadjusted. direct measurement, unadjusted.

ILOsILOsIntended Learning OutcomesIntended Learning Outcomes

a.k.a., Learning Objectivesa.k.a., Learning Objectives

Androgen physiologyAndrogen physiology Androgen changes with agingAndrogen changes with aging Syndrome of ADAMSyndrome of ADAM Effects of testosterone Effects of testosterone

replacementreplacement Practice guidelinePractice guideline

Bonus Bonus factoidfactoid

Licorice Licorice Testosterone Testosterone

NEJM 1999;341:1158

The lecture ends here!

Questions?Answers $0.25Answers requiring thought $1.00Correct answers $2.50

Comments?

If you want to read If you want to read more …more …

Liverman CT, Blazer DG, eds. Testosterone and aging: clinical Liverman CT, Blazer DG, eds. Testosterone and aging: clinical research directions. Washington, D.D.: National Academies research directions. Washington, D.D.: National Academies Press, 2004. (IoM report)Press, 2004. (IoM report)

Laumann EO, PaikA, Rosen RC. Sexual dysfunction in the US: Laumann EO, PaikA, Rosen RC. Sexual dysfunction in the US: prevalence and predictors. JAMA 1999;281:537-44. Correction prevalence and predictors. JAMA 1999;281:537-44. Correction 281:1174.281:1174.

Rhoden EL, Morgentaler A. Risks of testosterone replacement Rhoden EL, Morgentaler A. Risks of testosterone replacement therapy and recommendations for monitoring. NEJM therapy and recommendations for monitoring. NEJM 2004;350:482-92.2004;350:482-92.

Calof OM, Singh AB, Martin LL, et.al. Adverse events Calof OM, Singh AB, Martin LL, et.al. Adverse events associated with testosterone replacement in middle-aged and associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebo-controlled older men: A meta-analysis of randomized, placebo-controlled trials. Journal of Gerontology 2005;11:1451-1457.trials. Journal of Gerontology 2005;11:1451-1457.

Full bibliography available on request: nmj@medicine.wisc.eduFull bibliography available on request: nmj@medicine.wisc.edu