Applying Endocrine Society Guideline for the Diagnosis and Treatment of Hypogonadism Shalender Bhasin, MDProfessor of Medicine, Harvard Medical SchoolDirector, Research Program in Men’s Health: Aging and MetabolismDirector, Boston Claude D. Pepper Older Americans Independence CenterBrigham and Women’s Hospital

Outline of the Presentation

◆Complexities in the diagnostic work up– Factors contributing to the risk of misclassification– Steps to increase diagnostic accuracy

◆Emerging androgen deficiency syndromes◆Age-related decline in testosterone levels◆Potential risks of TRT ◆Optimizing benefit to risk ratio by standardized monitoring

Definition“Hypogonadism in men is a clinical syndrome that results

from failure of the testes to produce physiological levels of testosterone (androgen deficiency) and the normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis”

Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA. J Clin Endocrinol Metab. 2018;103:1715-1744.

— The Endocrine SocietyClinical Practice Guidelines

Two parts to the diagnostic evaluation:1. Ascertainment of signs and symptoms2. Ascertainment of low testosterone levels

Which of these men has hypogonadism?24-year old man is evaluated for failure to develop secondary sex characteristics. He is unable to smell. PE: eunuchoidalproportions, few facial hair, female pattern escutcheon, penis 3 cm, and testes 4 mL bilaterally. Total T 70 ng/dL, free T 10 pg/mL, LH 1 U/L, FSH 0.5 U/L. MRI: poorly developed olfactory bulbs.

Control Patient

– In such men with severe hypogonadism, the risk of misclassification was low even prior to the advent of RIAs, and the benefits of TRT were readily apparent.

Fuller Albright

Which of these men has hypogonadism?1. An obese 58-year old man, a father of two children, complains of

difficulty in achieving and maintaining erections. BMI 40 kg/m2, normal proportions and hair, phallus 9 cm, testes 25 ml b/l. Total T 270 ng/dL, LH 5 U/L, FSH 4 U/L.

2. 68-year old man complains of decreasing sex drive, energy and memory. PE normal. T 290 ng/dL, LH 6 U/L, FSH 5 U/L.

Testosterone Prescribing Patterns in the US

◆ 80% of prescriptions are being written for men 40 to 74 years.

◆ A majority of testosterone prescriptions are written for men who have either low normal, or only slightly reduced T level.

Bhasin S, Wu F. Nature Clin Pract Endocrinol Metab 2006 2, 529 Jasuja GK, et al, Med Care. 2015;53:746-52; Nguyen CP, et al., N Engl J Med 2015;373:689-691

1. High risk of misclassification in both direction2. The efficacy and safety of testosterone therapy in men with T levels slightly

below the cut-point remains unknown.

Low T, high LH(hypergonadotropic)

Low T, low or inappropriatelynormal LH (hypogonadotropic)

Three-Step Workup of Men With Androgen Deficiency

Measure LH and FSH

Primary testicular dysfunction• Obtain karyotype to exclude

Klinefelter’s syndrome

• Rule out systemic illness• Measure prolactin and ferritin• Evaluate other pituitary hormones• MRI scan• Identify by pattern recognition

Confirm Low Total T and/ or Free T

Measure Fasting, Early AM Total T and if indicated Free T

Ascertain signs and symptoms; exclude systemic causesSTEP 1

STEP 2: Ascertain T Def.

STEP 3: Ascertain Cause

Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA. J Clin Endocrinol Metab. 2018;103:1715-1744.

Sources of Diagnostic Imprecision and Inaccuracy

◆ Non-specificity of signs and symptoms◆ Variation in circulating T levels

– Biological factors: genetic factors, binding protein concentrations, secretory rhythms of testosterone

– Methodological factors: assay imprecision and inaccuracy, differences in calibrator

◆ Poorly-derived reference ranges

Symptoms and Signs with Higher Specificity

◆ Incomplete or delayed sexual development ◆ Loss of body hair (axillary and pubic) hair ◆ Very small testes (less than 6 mL)◆ Sexual symptoms:

– Reduced sexual desire (libido) and activity– Decreased spontaneous erections– Erectile dysfunction

Bhasin S et al. J Clin Endocrinol Metab. 2010;91:1995-2010; Wu FCW et al. N Engl J Med 2010;363:123-135

Day-to-Day Variability in T Levels During Repeated Testing

VISIT 1 VISIT 2 ng/dL <300 ng/dL > 300 ng/dL TOTAL

<300 16 5 21> 300 7 93 100TOTAL 23 98 121

Brombilla et al, Clin Endocrinol 2007

The diagnosis of androgen deficiency should not be based on a single testosterone measurements.

Inter-Laboratory and Inter-Assay Variability in Testosterone RIAs

Instrument/Assay Laboratories(n) Mean SD CV Median

RangeLow High

Abbot Architect 11 243.5 13.8 5.7 243 219 262

Bayer ACS:180 83 317.6 39 12.3 314 227 410

Bayer Centaur 231 324.0 41.5 12.8 319 234 454

Bayer Immuno-1 43 300.6 16.7 5.6 300 254 335

Beckman Access/2 98 297.8 15.3 5.1 298 239 330

Diagnostic Systems 10 352.7 80.1 22.7 375 177 440

DPC Coat-a-Count 76 277.8 34.2 12.3 281 196 363

DPC Immulite 86 232.0 32.9 14.2 228 160 330

DPC Immulite 2000 83 210.8 33.5 15.9 215 130 299

Roche Elecsys/E170 87 349.9 23.0 6.6 348 299 408

Ortho Vitros ECi 54 282.3 15.8 5.6 280 254 324

All Instruments 891 293.6 56.2 19.1 297 130 508

Wang C et al. J Clin Endocrinol Metab. 2004;89:534-543.

Reducing Measurement Error by Using Accurate Assays Certified by CDC’s Hormone Standardization Program (HoSt)

◆ Measure T using an accurate assay.◆ LC-MS/MS assays provide high precision and accuracy esp. in

the low range.◆ Certification by CDC’s HoSt Program:

– The participating assays are bench-marked to a higher order reference method and calibrator.

– Total T measured by LC-MS/MS in CDC-certified laboratories are similar.

Bhasin et al. Steroids. 2008;73(13):1311-7; Bhasin S et al. J Clin EndocrinolMetab. 2010;91:1995.

Defining Low T? Need for Rigorous Reference Ranges

◆ Rigorously determined reference ranges are:– Essential for identifying individuals as

“healthy” and “diseased” Problems:– Vary widely across laboratories– Population-based reference ranges

not available

What is low? What is high?

Harmonized Testosterone Reference Range◆ T assays from four epidemiologic studies cross-calibrated by

CDC, and testosterone levels harmonized using Deming’s regression.

◆ Age-adjusted distribution of T levels very similar across the 4 epi studies: FHS, MrOS, EMAS, and Belgian Sibship Study

◆ 2.5th percentile ~263 ng/dL (9.2 nmol/L); 97.5th percentile 914 ng/dL (33 nmol/L).

Travison TG, Vesper HW, Orwoll E, Wu F, Kaufman JM, Wang Y, Lapauw B, Fiers T, Matsumoto AM, Bhasin S. J Clin Endocrinol Metab. 2017;102(4):1161-1173.

Harmonized Testosterone Levels

Impact of Assay Precision (Inter-Assay CV) on Clinical Decision Making

20-year-old man requests evaluation for sexual dysfunction. He is well virilized; testicular volume 20 mL. Serum testosterone 299 ng/dL. Lower limit of normal 300 ng/dL in an RIA with 15% CVØWhich is the true T concentration in the patient?

» 299 ng/dL» 240 ng/dL» 360 ng/dL» Cannot tell from the information provided

Binding Protein Abnormalities◆ An obese 35-year old man, a father of two children, complains

of difficulty in achieving and maintaining erections. BMI 40 kg/m2, normal proportions and hair, phallus 9 cm, testes 25 ml b/l.

Total T 280 ng/dL, LH 5 U/L, FSH 4 U/L.

What diagnostic test/s would you order at this time?

The Importance of Measuring the Free or Biologically Active Fraction

◆ Binding protein levels affected by aging, infl., obesity, hypo and hyperthyroidism, liver disease, and genetics.

◆ Binding protein concentrations may be independently associated with metabolic outcomes.

◆ Genetic differences in binding protein concentrations may contribute to ethnic/ racial differences in testosterone levels.

Bhasin et al, Diabetes Care 2013; Powe et al NEJM 2013

Albumin-bound

Sp Bindingprotein

Free

Measurements of free analyte is necessary for clinical decision making when binding protein conc are altered!

Methods for Assessing Free Testosterone (FT) Levels

Two ways of assessing FT levels

Direct Measurement:- Tracer analog methods - Equilibrium dialysis (reference method)- Ultrafiltration - Ammonium sulfate precipitation

Calculated FT (cFT)- Calculation based on Total T,

SHBG and albumin- Empirically-derived equations

A Dynamic Multi-Step Ensemble Model of Testosterone’s Binding to SHBG with Allostery

Vermeulen’s Model

Multi-Step Ensemble Allostery ModelZakharov, Bhasin, Jasuja.

Mol Cell Endo 2014

Heritability and Genetic Determinants of Testosterone Levels in Men

◆ Strong heritability: genetic factors account for 65% of variation in serum T levels

◆ Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in serum T and increased risk of low testosterone.

◆ rs6258 polymorphism affects SHBG binding affinity for T and the measured free T fraction.

Rs6258 affects SHBG binding to T

Ohlsson et al, PLOS Genet 2011

Use Ancillary Data to Support the Diagnosis

◆ 26-year old man is being evaluated for sexual dysfunction. He started shaving at age 15 and became sexually active at age 18. He appears well virilized, but has bilateral breast enlargement. His total T is 325 ng/dL, free T 70 pg/ml.

◆ Is he hypogonadal? ◆ What additional test/s would you order?

Emerging Androgen Deficiency Syndromes in Men

◆ Androgen deficiency associated with opioid use◆ Androgenic-Anabolic Steroid Withdrawal

Hypogonadism

High Prevalence of Low Testosterone, Sexual Dysfunction, and Osteoporosis in Patients Receiving Opioid Analgesics

Bliesener N et al. JCEM 2005;90:203-206

Low BMD in Patients Receiving Methadone

Maintenance• T-scores <−2.5 (osteoporosis

range) in 35% • BMD <-1.0 and >−2.5

(osteopenia range) in 48%

Kim et al, Drug and Alcohol Depend 2006;85: 258-262

Lower T in Methadone-Treated Men

Sexual Dysfunction in Methadone-Treated Men

Osteoporosis in Methadone-Treated Men

Anabolic Steroid Withdrawal Hypogonadism ◆ 24 men, 35-55 years, with >2 years of life time AAS use◆ Mean T levels in former users (319±163 ng/dL) were lower

than in healthy young men in FHS (723±221 ng/L). ◆ 14 had symptoms of hypogonadism and low T; 5 of 24 had

levels <200 ng/dL; 5 reported major depression episodes

Coward RM, et al. J Urol. 2013; Rahnema C, et al, Fertil Steril 2014; Kanayama et al, Addiction 2015

After prolonged use of large doses of AAS, the recovery of HPT axis may be incomplete or may not occur at all leading to AAS Withdrawal Hypogonadism In some men’s health clinics, AAS withdrawal hypogonadism has emerged as important cause of androgen deficiency.

Klinefelter Syndrome◆ 47, XXY karyotype: nondysjunction during

meiosis; 46, XY/47,XXY) more common◆ Approx. 1 in 500 males◆ Presentation:

– Childhood: behavioral and learning problems– Adulthood: Infertility or androgen deficiency

◆ Phenotype: – Normal pubertal development– Very small testes, eunuchoidal proportions,

gynecomastia– Normal performance IQ, but low verbal IQ

Excess Morbidity and Mortality in Klinefelter’sSyndrome

◆ KS patients are at increased risk for:– Overall mortality – Breast cancer– Certain types of non-Hodgkin’s lymphomas– Lung cancer– Autoimmune diseases

◆ Lower risk for prostate cancer

Swerdlow et al JNCI 2005 Aug 17;97(16):1204-10; Swerdlow et al JCEM 2005; 2005 Dec;90(12):6516-22

Men with KS should undergo periodic screening for breast cancer.

Golden Rules for an Accurate Diagnosis of Androgen Deficiency Syndrome

◆ Use an accurate assay (preferably an LC-MS/MS assay), a CDC-certified lab, and rigorously-derived reference range.

◆ Do not make a diagnosis of AD based on a single T measurement.

◆ Do not make a diagnosis of AD based only on T level.◆ Measure free T using an accurate method when binding protein

abnormality is suspected.◆ Use ancillary data (testicular volume, LH, FSH levels) to aid in the

diagnosis.

Bhasin and Wu. Nature Rev Endocrinol 2010

◆Age-Associated Decline in Serum Testosterone Levels in Older Men

Age-Associated Decline in Testosterone Levels

Percent of Community-Dwelling Older Men with Unequivocally Low Testosterone Level

Study PI # Men > 65

% Men with T <250 ng/dL

FHS Bhasin 1870 12.1%MrOs Orwoll 2623 10%EMAS Wu 1080 7.3%CHS Hirsch 639 14.3%

Bhasin et al, JCEM 2011; Orwoll et al, JCEM 2009; Wu et al, NEJM 2010; Hirsch et al, JCEM 2009

Prevalence of late-onset hypogonadism defined by symptoms and a total T level <8 nmol/l in the EMAS was 3.2% for men 60–69 years and 5.1% for men 70–79 years.

Epidemiological Data: Weak Association of Low T and Outcomes◆ Positively associated with:

– Muscle mass (Baumgartner 1998; Melton 2000), strength (Morley 2000), and physical function (MMAS 2005)

– Sexual desire (Beutel 2005; Travison 2005)– aBMD, vBMD, bone geometry, fracture risk (Khosla 2005)

◆ Negatively associated with:– CAD (Wu 2003; von Eckardstein 2003)– Visceral fat (Seidell et al)– Metabolic syndrome– Diabetes mellitus (Haffner 1996; Stellato)– Falls and fractures (Orwoll 2007)– Mortality (Shore et al 2006)

Major RCTs of Testosterone’s Effects in Older AdultsTrial Eligibility Baseline T Symptom

RequirementOutcomes

TTrials – PhysicalFunction Trial (n=780), 1 year

>65 years Average of two T levels < 275 ng/dL

Mobility difficulty, 6MWS <1.2 m/sec

6MWD, PF10, and PGICFACIT-1

TEAAM Trial (n=308); 3 years

>60 years TT < 400 ng/dLand/or free T <50 pg/mL

No symptom requirement

Muscle mass, strength and power, physical function, self-reported function

TOM Trial (n=209); 6 months

65 years or older

TT <350 ng/dLand/ or free T <50 pg/mL

Self-reported mobility difficulty, SPPB 4 to 9

LBM, strength and power, loaded and unloaded gait speed and stair climbing power, fatigue, disability, PGIC

Wu et al (n= 274); 6 months

Men, 65 years or older

TT <340 ng/L, or free T <83 pg/mL

Frail and intermediate frail

LBM, strength, muscle strength, physical function, and self-reported quality of life

Emmelot-Wonk Trial (n=237); 6 months

60 to 80 years

TT <400 ng/dL No symptom requirement

LBM, strength, TUG, self-reported functional mobility

Nair et al (n=58); 2 years

60 or older Bio-T < 103 ng/dL No symptom requirement

LBM, strength, VO2max, BMD

Snyder et al, NEJM 2016;374:611-24; Basaria et al, JAMA 2015;314:570-81; Basaria et al, NEJM 2010;363:109-22.; Srinivas Shankar et al, JCEM 2010;95:639-50; Emmelot-Wonk et al, JAMA 2008;299:39-52; Nair et al, NEJM 2006;355:1647.

Lessons Learned from Recent Large RCTs about Testosterone’s Efficacy: Sexual Function◆ No beneficial effects in men who had normal T levels and no

symptoms◆ TRT improved overall sexual activity, sexual desire, erectile

function, and satisfaction with erectile function in older men with low T levels and decreased libido.

◆ TRT does not improve ejaculatory function or erectile response to PDE5Is.

Snyder et al, NEJM 2016;374:611-24; Basaria et al, JAMA 2015;314:570-81; Brock et al, J Urol 2016;195:699-705; Basaria et al, NEJM 2010;363:109-22.

Muscle Mass, Muscle Performance and Physical Function

◆ Testosterone administration increases:– Skeletal muscle mass, – Maximal voluntary strength and muscle power, – VO2peak

– Self-reported function– Stair climbing speed and power; and walking ability

◆ The anabolic effects of T on muscle mass and strength are augmented by resistance exercise training but not by protein supplementation.

Snyder et al, NEJM 2016;374:611-24; Basaria et al, JAMA 2015;314:570-81; Basaria et al, NEJM 2010;363:109-22; Srinivas Shankar et al, JCEM 2010;95:639-50; Emmelot-Wonk et al, JAMA 2008;299:39-52; Nair et al, NEJM 2006;355:1647.

T improves Areal and Volumetric Bone Density and Estimated Bone Strength

Snyder et al JAMA Intern Med. 2017;177:471-479; Tracz et al, J Clin Endocrinol Metab. 2006;91:2011-6.

Volumetric Bone Density Estimated Bone StrengthVertebral Areal Bone DensityT Trials DataMeta-Analysis

Effects on Other Endpoints

Endpoint Findings of RCTs

Anemia Corrected unexplained anemia of aging and anemia of other causes

Depressive symptoms Small improvements in depressive symptoms; weak evidence efficacy in late-onset PDD (dysthymia)

HRQOL Improves physical function domain score

Fatigue No improvement – problems with PROs

Cognition No improvement in cognition community-dwelling men; Efficacy in men with preclinical AD?

Basaria et al, NEJM 2010; Bhasin et al, JAMA Psych 2018; Snyder et al, JAMA IM 2017; Basaria et al, JAMA 2015; Huang et al, Lancet Diabetes Endocrinol 2016; Resnick et al, JAMA 2017; Travison et al, J Gerontol 2011

TRAVERSE Trial: Cardiovascular safety trial in 6,000 middle aged and older men at increased MACE risk treated with placebo or T for up to 5 years

Potential Adverse Effects Associated with Testosterone Therapy

Difficulties in Drawing Strong Inferences About Testosterone’s Long Term Safety◆ Relatively small sample size of the RCTs◆ Short duration of most trials◆ General under-reporting of AEs in clinical trials◆ CV and prostate events not ascertained in a structured

manner nor adjudicated in most trials◆ Older adults at increased risk of prostate and CV events

have generally been excluded from RCTs.

Adverse Events Associated with TRT in Older Men

◆ Erythrocytosis the most frequent AE.◆ No significant change in LUTS in men with IPSS < 21.◆ Increased risk of detection of subclinical prostate disease. ◆ The trials not large enough or long enough to evaluate effects

on MACE and prostate cancer risk. ◆ No clear evidence that TRT increases the risk of MACE or

prostate cancer.

Bhasin et al, J Androl 2003; Snyder et al, NEJM 2016;374:611-24; Basaria et al, NEJM 2010;363:109-22. Basaria et al, JAMA 2015;314:570-81; Huang et al, Lancet Endocrinol Diab 2016; Travison et al, J Gerontol 2011; Spitzer et al, Nature EndocrinolMetab 2013

Managing Erythrocytosis During Testosterone Therapy

◆ Significantly higher frequency of erythrocytosis (hematocrit >54%) compared to placebo (RR: 8.14, CI 95% [1.87, 35.40])

◆ Increases in Hb/Hct related to dose and circulating level◆ If hematocrit rises above >54%

– Hold T dose until hematocrit drops to a safe level, evaluate for other causes of erythrocytosis, and then restart at a lower dose

Title Here (Go Header & Footer to edit this text) 39

ES

Testosterone and Erythropoiesis◆ Erythrocytosis the most frequent AE associated with TRT

– Effects are related to T dose and concentrations– Greater increments in older men

◆ Mechanisms: – T stimulates iron-dependent erythropoiesis in the bone marrow– Suppresses hepcidin transcription and increases iron availability– Effects on RBC survival

Guo et al, Aging Cell 2014; Guo et al, JGMS 2017; Guo et al, 2019; Bhasin et al, 2001, 2007 ; Coviello et al, 2008; Bachman et al, JCEM 2010.

Managing Erythrocytosis During Testosterone Therapy

41

What is an unsafe level of Hematocrit (Hct)?Hct Relationship With Plasma Viscosity and O2 Delivery

42

Exponential increase in viscosity with increasing hematocrit

Bloo

d R

elat

ive V

iscos

ity

Hematocrit % Hematocrit %

Fedde and Wood. Respir Physiol. 1993;94(3):323-35.

10

9

8

7

6

5

4

3

2

1

020 40 60 800

11.3 sec-1

90 sec-1

225 sec-1

Shear Rate

Hematocrit relationship with oxygencarrying capacity and transport

Oxy

gen

Flow

(%/cP

)

Cardiovascular Risk of T TherapyBiological Plausibility: Consistent Evidence

Potential CV Risks:◆ Hematocrit◆ HDL cholesterol ◆ Platelet aggregation◆ Sodium retention◆ Smooth muscle

proliferation◆ VCAM expression

Potential CV Benefits:◆ Vasodilator effect

– Increased coronary and penile blood flow

◆ Whole body fat–SC and visceral

◆ Vascular reactivity◆ Shortens QTc interval

◆ Several recent retrospective analyses of EMR data of men on TRT have yielded conflicting results.

◆ Limitations– Heterogeneity of study populations, intervention duration, and

study designs – Variable definitions, ascertainment of CV outcomes– Unclear treatment indications, treatment regimens,

testosterone levels, and exposure – Residual confounding: Study groups differed in CV risk factors

◆ Overall Assessment– Inconsistent findings across studies – Difficult to draw inferences

Mixed Results from Observational and Pharmacovigilance Studies of TRT and Mortality/CV Outcomes

Vigen et al. JAMA. 2013;310(17):1829-36. Shores et al. J Clin Endocrinol Metab. 2012;97(6):2050-8.

Study (Event, Statistic)

TRT Placebo OR / RR(95% CI)events N events N

Calof 2005 (CV, OR) 18 651 16 433 1.14 (0.59, 2.20)

Ruige 2013 (CV, RR) NR 1289 NR 848 1.64 (0.77, 3.47)

Xu 2013 (CV, OR) 115 1733 65 1261 1.54 (1.09, 2.18)

Haddad 2007 (CV, OR) 14 161 7 147 1.82 (0.78, 4.23)

Corona 2014 (CV, OR) 126 1944 84 1390 1.07 (0.69, 1.65)

Xu 2013 (Serious CV, OR) NR 1733 NR 1261 1.61 (1.01, 2.56)

Corona 2014 (MACE, OR) 31 1895 20 1341 1.01 (0.57, 1.77)

Fern-Bal 2012 (Death, RR) 36 261 23 215 1.12 (0.70, 1.81)

Xu 2013 (Death, OR) 22 1733 11 1261 1.42 (0.70, 2.89)

0.1 1 10

Results from Meta Analyses of TRT and MACE

NR = Not ReportedDecreased risk Increased risk

TRT and Atherosclerosis Progression in Older Men: The TEAAM Trial

CCA- Intima Media Thickness, mm Coronary Artery Calcium, AUs

Basaria et al, JAMA 2015;314(6):570-81.

Effect of Testosterone on Coronary Artery Plaque Volume in the TTrials

Budoff et al. Testosterone treatment and coronary artery plaque volume in older men. JAMA. 2017;317:708-716.

Prostate Effects: Inherent Bias Towards Detection of Greater Number of Prostate Events in T-treated Men

◆ No evidence that T causes prostate cancer◆ No evidence of worsening of lower urinary tract symptoms◆ T increases PSA and prostate biopsies usually triggered by

PSA increments in clinical trials◆ PSA increments more likely in T-treated men than in

placebo-treated men leading to greater number of biopsies and detection of subclinical prostate events.

Calof et al J Gerontol 2006; Spitzer et al, Nature Rev Endocrol 2013; Ponce OJ, J ClinEndocrinol Metab. 2018 Mar 17. doi: 10.1210/jc.2018-00404.

Monitoring of Testosterone Therapy

49

Baseline 3 – 12 months Annually

Symptoms X 3 – 6 months X

Adverse events X 3 – 6 months X

Testosterone levels

X 3 – 6 months X

Hb/Hct X 3 – 6 months X

PSA / DRE* X 3 – 12 months X

*Prostate monitoring has some risks. Therefore, the decision to monitor should be a shared decision after appropriate discussion of risks and benefits.

Bhasin S, et al. J Clin Endocrinol Metab. 2018: epub ahead of print

Enormous Variation in On-Treatment T Levels Contributing to Poor Adherence

50% of Men have Out-of-Range T Levels on Initial T Gel Dose

50% of Men Discontinue T Therapy within 3 Months

Shoenfeld et al, J Sex Med 2013;10:1401

Synthesis of Data and Conclusions◆ Important to distinguish between classical

hypogonadism and age-related decline◆ In young men with classical hypogonadism,

TRT improves symptoms with low AE frequency

◆ In older men with age-related decline or frailty, TRT improves sexual function, anemia, bone density and quality, muscle mass, strength and some measures of function, but long-term benefits in improving hard outcomes and risks have not been demonstrated.

Benefits

Risks

An Investigator’s prayer: O Great Spirit! Please, bless my partners, who make me look smarter than I am, and soften the hearts of our reviewers.

ClinicalTrials◆ Shehzad Basaria◆ GraceHuang◆ AnnaRoss◆ MattSpitzer◆ RichEder◆ EricBachman

Biostatistician◆ TomTravison◆ KarolPencina

Mechanisms◆ RaviJasuja◆ WenGuo◆ CarloSerra◆ Rajan Singh

ExercisePhysiology♦ TomStorer♦ ReneeMiciek♦ LindaWoodhouse♦ ErinWoodbury♦ JenniferMcKinnon

BehavioralStudies♦ PeterGray♦ RayTricker

EpidemiologicStudies♦ GuneetKaur♦ TomTravison♦ AndreaCoviello

HormoneAssays♦ LimingPeng♦ HeleneStroh♦ Anqi Zhang

Collaborators•RichardCasaburi•HarrisonPope•VasanRamachandran•JoanneMurabito•KevinYarasheski•FredSattler•StefanArver•FredWu•EricOrwoll

Grant Support: NIA, NIDDK, NINR, NICHD, PCORI, FNIH, Pepper Center P30