APPROACH TO HYPOGONADAL MEN. Michael S. Irwig, M.D. Director, Center for Andrology Division of Endocrinology & Metabolism

APPROACH TO HYPOGONADAL MEN Michael S. Irwig, M.D. Director, Center for Andrology Division of Endocrinology & Metabolism

Disclosures Pharma-Free Presentation

My andrology clinic

Controversy with Testosterone Endocrine Society s Clinical Practice Guidelines EVIDENCE RECOMMENDATIONS QUALITY High 0 Moderate 0 Low 11 Very Low 21 Bhasin S, et al. J Clin Endocrinol Metab 2010

Controversy with Testosterone Endocrine Society s Clinical Practice Guidelines EVIDENCE RECOMMENDATIONS QUALITY High 0 Moderate 0 Low 11 Very Low 21 No distinction between aging and disease-based androgen deficiency due to hypothalamic, pituitary or testicular pathology No cut point for a low testosterone No clear definition of symptomatic Bhasin S, et al. J Clin Endocrinol Metab 2010

Controversy with Testosterone September 2014 -- the FDA s Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Committee voted 20-1 that the indication should be tightened that TRT is NOT indicated for age-related declines in testosterone. We don t really know whether aging-associated low testosterone is in fact a disease at all A. Michael Lincoff, MD, Vice Chairman of cardiovascular medicine, Cleveland Clinic. Internal Medicine News 2014

Case # 1 A 48 year old man is referred for consultation regarding management of a low total testosterone of 171 ng/dl (250-827) Past medical history: hypertension, hyperlipidemia, prediabetes Medications: olmesartan-hctz, rosuvastatin, vitamin D Vitals: BP 147/77; BMI 31 Physical: normal exam; testes 20 cc bilaterally Normal puberty Married and has fathered 2 children ROS + difficulty maintaining an erection irritability

Erectile Dysfunction Assessment Abridged International Index of Erectile Function Short instrument of five questions on a likert scale (1,2,3,4,5) Sum the numbers to get the score 5-7 severe 8-11 moderate 12-16 mild-moderate 17-21 mild 22-25 none Only administer if man has had sexual intercourse in past 6 months; for gay men inquire about sexual practices Rosen RC et al. Int J Impot Res 1999

Any other signs or symptoms to inquire about?

Signs & Symptoms Associated With a Low Testosterone libido erectile dysfunction regression of secondary sex characteristics osteoporosis muscle strength depression depressed mood lethargy inability to concentrate sleep disturbance irritability decreased interest in activities Second Annual Andropause Consensus Meeting. The Endocrine Society 2001

What s a low libido?

Sexual Desire (Libido) Dopamine Norepinephrine Oxytocin Serotonin Opioids Endocannabinoids Pfaus J. J Sex Med 2009

Androgen Deficiency Boston Area Community Health Survey N = 1,413 men aged 39-79; white, black and Hispanic Low total T < 300 ng/dl; low free T < 5 ng/dl Symptoms: 1 suggestive (ED, low libido, osteo) or 2 non-specific (lethargy, depression, etc) Araujo AB, et al. J Clin Endocrinol Metab 2008

Testosterone Levels & Symptoms European Male Aging Study (N=3200 men 40-79) 244 ng/dl 3 sexual symptoms + total testosterone < 317 ng/dl AM full erections Erections (get and keep) Think about sex Symptomatic 1/past month never or sometimes 3 times/month Wu FC, et al. NEJM 2010

How many hours do you sleep each night?

Testosterone & Sleep 700 600 500 400 ng/dl Leproult R, et al. JAMA 2011

Do you snore?

Sleep Apnea Screening STOP-BANG Scoring Tool 1) Snoring loudly 2) Tired, fatigued, sleepy during the daytime 3) Has anyone Observed you stop breathing? 4) High blood Pressure 5) BMI > 35 6) Age > 50 7) Neck circumference > 17 in males 8) Male Gender Chung F et al. J Anesthesiology 2008

The patient is concerned about his low T level. What do you do next?

Daily Testosterone Variability Spratt DI, et al. Am J Physiol 1988

WHAT TEST BEST REFLECTS HIS ANDROGEN STATUS? A) AM total testosterone by LC/MS B) AM bioavailable T or free T by equilibrium dialysis C) AM free T by analog immunoassay D) They are all similar E) Ask the 8 ball

Sex Hormone Binding Globulin FREE SHBG ALBUMIN Bioavailable testosterone = free + albumin bound

Which is Better: Total or Free? European Male Aging Study (N=3200 men age 40-79) (300 ng/dl) (6.3 ng/dl) Free T regulates LH secretion Antonio L, et al. J Clin Endocrinol Metab 2016

Case # 1 Initial labs: total testosterone 171 ng/dl (250-827) AM FASTING LABS Total testosterone 212 ng/dl (348-1197) Bioavailable testosterone 100 ng/dl (95-350) So how do you interpret his T levels?

Testosterone and BMI European Male Aging Study (N=3200 men 40-79) Wu FC, et al. J Clin Endocrinol Metab 2008

Sex Hormone Binding Globulin Obesity Hypothyroidism Androgens Progestins Glucocorticoids Nephrotic syndrome Aging Hyperthyroidism Androgen deficiency Estrogens Anticonvulsants Hepatic cirrhosis HIV

Testosterone is a Prohormone Testosterone aromatase 5 α reductase Estradiol (E2) Dihydrotestosterone (DHT)

Do you want to prescribe testosterone therapy? Yes No

Case # 1 MY RECOMMENDATIONS Begin an exercise regimen and lose weight (goal weight of 240 215 lbs) Sleep study to assess for sleep apnea

Weight Loss & Testosterone 173 ng/dl 115 ng/dl 58 ng/dl Grossmann M. J Clin Endocrinol Metab 2011

Case # 1 FOUR MONTH FOLLOW-UP APPOINTMENT He reports exercising twice a week for an hour (cardio & weights) He gained 7 lbs since the last visit He reports an improvement to his energy, physical functioning, erectile function and marital relationship Referral to a nutritionist SUBSEQUENT PLANS Reassess his testosterone level and HbA1c after he has lost weight

Case # 1 Search for reversible causes of ED MEDICATIONS Anticonvulsants: carbamazepine, phenytoin, primidone Antidepressants: amitriptyline, amoxapine, clomipramine, imipramine, nortriptyline, phenelzine, fluoxetine, fluvoxamine, paroxetine, sertraline Antipsychotics: chlorpromazine, haloperidol, thioridazine Barbiturates Benzodiazepines Antihypertensives: atenolol, clonidine, hydralazine, labetalol, methyldopa, metoprolol, propranolol, verapamil Diuretics: amiloride, chlorthalidone, spironolactone, thiazides NSAIDS: naproxen Anticholinergics: atropine, diphenhydramine, scopolamine Antispasmodics: baclofen, hypnotics

Case # 2 A 30 year old man is referred by his NP for consultation regarding management of several symptoms over 3-4 years: Decreased libido Nervousness Fatigue Cold intolerance Confusion Insomnia Normal puberty; single and has not attempted to father children He denies any causes of primary or secondary hypogonadism Past medical history: hyperlipidemia Medications: mind & memory supplements (ginkgo, L-carnitine, St. Johns Wort); vitamins A,B,C, D and E; zinc Vitals: BP 148/77; BMI 27 Physical:? gynecomastia; testes 8 cc bilaterally

Case # 2 OUTSIDE LABS Total testosterone 367 ng/dl (348-1197) Free testosterone 73 pg/ml (52-280) Bioavailable T 185 ng/dl (128-430) Estradiol 37.6 pg/ml (7.6-42.6) LH 5.1 (1.7-8.6) FSH 7.0 (1.5-12.4) What do you do next?

Depression Screening Patient Health Questionnaire 9 (PHQ-9) Over the past 2 weeks, how often have you been bothered by? 1) Little interest or pleasure in doing things 2) Feeling down, depressed, or hopeless 3) Trouble falling or staying asleep, or sleeping too much 4) Feeling tired or having little energy 5) Poor appetite or overeating 6) Feeling bad about yourself or that you are a failure or have let yourself or family down 7) Trouble concentrating on things, such as reading the newspaper or watching TV 8) Moving or speaking so slowly that other people could have noticed 9) Thoughts that you would be better off dead or of hurting yourself in some way 0= not at all 1=several days 2= > half of days 3= nearly every day Kroenke K et al. J Gen Intern Med 2001

Depression Screening Patient Health Questionnaire 9 (PHQ-9) Over the past 2 weeks, how often have you been bothered by? 0= not at all 1=several days 2= > half of days 3= nearly every day Sum the scores (range 0-27) Using the mental health professional interview as the criterion standard, a score 10 had a sensitivity of 88% and a specificity of 88% for major depression. Kroenke K et al. J Gen Intern Med 2001

Depression Screening

Men with Borderline T Levels Total testosterone levels between 200-350 ng/dl (6.9-12 nmol/l) EXERCISE SESSIONS/WEEK N=200 None 51% 1-3 27% 4 22% WEIGHT STATUS Underweight 2% Normal 16% Overweight 39% Obese 43% DEPRESSION AND/OR DEPRESSIVE SYMPTOMS (PHQ 9 10) 56% Westley C, et al. J Sex Med 2015

Case # 3 A 40 year old man presents to clinic with complaints of lower energy and libido than normal. He works 2 jobs and has 1 day off a week. Past medical history: unremarkable. Medications: none Vitals & Physical: BP =124/75; BMI 30; otherwise normal exam An afternoon total testosterone by LC/MS done by his general physician was 370 ng/dl [12.8 nmol/l] (normal range 348-1197 ng/dl [12-42 nmol/l]). As it turns out, he had a total testosterone measured two years ago which was 625 ng/dl (21.7 nmol/l). He is concerned that his symptoms correlate with the decline in his testosterone levels. He believes that his testosterone is low for a man his age. He is interested in a trial of testosterone therapy.

Case # 3 WHAT DO YOU NEXT? A) Obtain an AM total testosterone by LC/MS B) Obtain an AM fasting bioavailable T and SHBG C) Prescribe 3 month trial of testosterone D) Educate the patient

Case # 3 WHAT DO YOU NEXT? A) Obtain an AM total testosterone by LC/MS B) Obtain an AM fasting bioavailable T and SHBG C) Prescribe 3 month trial of testosterone D) Educate the patient DOCTOR (dok ter) Teacher (derived from Latin)

Case # 3 WHAT IS THE MEAN TOTAL TESTOSTERONE LEVEL AMONG HEALTHY 40 YEAR OLD MEN? OLDER MEN YOUNGER MEN 350 450 550 650 750 850 950 1050 1150 12 15.6 19 26 33 ng/dl nmol/l

Current Philosophy in Medicine

Can you recommend a supplement to boost my testosterone? Worldwide spending on nutritional supplements in 2006: $ 60,000,000,000

Contamination of Supplements Geyer H, et al. Int J Sports Med 2004

Case # 4 A 71 year old retired school bus driver with GERD, type 2 diabetes, & hyperlipidemia is referred for management of a low testosterone. Gradual erectile dysfunction; has not yet tried a PDE5I. Fewer AM erections than in the past His libido is lower than it once was ROS: Medications: fatigue, nocturia aspirin, atorvastatin, metformin, omeprazole, pioglitazone Vitals: BP 142/84, Weight 221 lbs, BMI 32 Physical: unremarkable Labs: AM total testosterone 269 ng/dl (348-1197) HbA1c 7.3% Repeat testosterone 291 ng/dl (348-1197)

So what does this patient want to know?

What is a Normal Testosterone? LOW NORMAL HIGH Cut points are arbitrary based on statistical percentiles rather than clinical correlations/evidence Different labs establish their own normal ranges Reference range is often based on lean adult men < 40 years and is usually not age adjusted

Proposed Levels of Normal T Massachusetts Male Aging Study REFERENCE RANGE: Using the 2.5% (roughly below 2 SD) of healthy men, the proposed normal lower limit for total testosterone was: Testosterone Age 251 ng/dl 40-49 216 ng/dl 50-59 196 ng/dl 60-69 156 ng/dl 70-79 Mohr BA, et al. Clin Endocrinol 2005

Consensus Statement on LOH American Society of Andrology (ASA) European Academy of Andrology (EAA) European Association of Urology (EAU) International Society of Andrology (ISA) Intl. Society for the Study of Aging Male (ISSAM) <230 ng/dl >350 ng/dl <8 nmol/l >12 nmol/l Usually benefits Repeat level No treatment from therapy Wang C, et al. Multiple Andro/Endo/Urology Journals 2008

Erectile Dysfunction Fazio L, et al. CMAJ 2004

Age is the # 1 Risk Factor for ED National Health and Nutrition Examination Survey (NHANES) (n =2126) ED definition sometimes able or never able 70 60 50 40 30 20 10 0 TOTAL 20-39 40-59 60-69 70+ AGE Selvin E et al. Am J Med 2007

Case # 4 My internist wanted me to ask you about testosterone replacement. Are there any cardiovascular risks? A) Very unlikely B) Possible increased risk of small magnitude C) Significant increased risk in men over 65 D) We have no idea. The studies have not been done.

Systematic Reviews >75 Testosterone trials 7 Systematic Reviews 1 Review of the Reviews Quality AMSTAR = tool to assess quality of systematic reviews Onasanya O, et al. Lancet Diabetes Endocrinol 2016

Systematic Reviews Calof 2005 Haddad 2007 Fernandez- Balsells 2010 Xu 2013 Borst 2014 Corona 2014 # trials Unspec 6 9 27 35 75 45 Albert 2016 N (treatment/ controls) CV events (treatment/ controls) Primary estimate (OR RR) Conclusion 651/433 161/147 715/456 1733/ 1261 1589/ 2114 3016/ 2448 3030/ 2298 18/16 14/7 47/30 115/65 131/87 31/20 116/92 1.14 (0.59-2.20) No assoc 1.82 (0.78-4.23) No assoc 0.91 (0.29-2.82) No assoc 1.54 (1.09-2.18) Risk 1.28 (0.76-2.13) No assoc 1.07 (0.69-1.65) No assoc 1.10 (0.86-1.41) No assoc Subgroup Analyses Risk with oral T only Risk in first 12 months Onasanya O, et al. Lancet Diabetes Endocrinol 2016

Take Home Points Recognize the non-specific nature of most symptoms of male hypogonadism Recognize the limitations of the reference range: it does not tell you what is normal Recognize the limitations of the guidelines given the low quality of most studies Clarify what does low libido represent to the patient Recognize the association between obesity and low SHBG (and total T) Educate men with borderline testosterone levels about mean levels and variability

Take Home Messages DO I PRESCRIBE THIS GUY TESTOSTERONE? SLEEP APNEA? OBESITY? ADEQUATE SLEEP? DEPRESSION? MEDICATION SIDE EFFECT?

Tool Box for Clinic ITEM Medication side effect Sleep apnea Erectile function Depression TOOL PDR, Lexicomp, Epocrates STOP Bang scoring tool Abridged international index of erectile function PHQ-9

Team Approach -- Resources PROBLEM RESOURCES Obesity Nutritionist Commercial weight loss programs Personal trainers Pedometers Depression Sleep apnea Severe erectile dysfunction Therapist, mental health Sleep specialist, CPAP Urology for intracavernosal injections, etc.

Questions mirwig@mfa.gwu.edu