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HRT and Andropause Taming the
Mythical BeastDr Ted Jablonski MD CCFP FCFP
61st ASA Banff, AB 2016
.
Dr. Ted JablonskiBSc Med, MD, CCFP, FCFP
• Clinical Associate at SouthernAlberta Institute of Urology, RVH Calgary
• Medical Director JABLONSKI Sexual Health and Wellness Clinic
• Member of SASHA • (Southern Alberta Sexual Health
Association)
Faculty/Presenter Disclosure
• Faculty/Presenter: Ted Jablonski
• Relationships with commercial interests: Grants/Research Support: Principal Investigator in Clinical studies
funded by Pfizer, Lilly, Cortria Speakers Bureau/Honoraria: Abbott Laboratories, AstraZeneca,
Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Edelman, Eli Lilly, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Merck Frosst, Mylan, Novartis, Paladin Labs, Pfizer, Sanofi-Aventis, Schering, Servier, Shire, Solvay, Takeda, Valeant, Watson
Consulting Fees: Not applicable Other: This presentation has received support from the Alberta
College of Family Physicians in the form of a speaker fee.
ACFP 61st ASADisclosure of Commercial Support
• Alberta Health Netcare• Alberta Health Services
Family Physician Recruitment eReferral AIM
• Alberta Health Services - Screening Programs • Alberta Medical Association
Sections of General Practice and Rural Medicine/ Billing
Physician and Family Support ProgramPractice Management ProgramPrimary Care Network Program
Management OfficeToward Optimized Practice
• Boehringer Ingelheim• Eli Lilly• Canada Diagnostic Centres
• Homewood Health Clinics• Janssen• LifeMark Health / Centric Health• NorthWest Healthcare Properties• Pfizer• Physician Learning Program• Physiotherapy Alberta - College + Association• Purdue• RHS Canada/The Snore Centre• Scotiabank • Surrey-North Delta Divisions of Family Practice • Trudell Medical International• University of Alberta• University of Calgary• Valeant Canada - Dermatology & Specialty• VitalAire Canada
• This program has received financial support in the form of sponsorship from:
• Potential for conflict(s) of interest: Those speakers/faculty who have made COI disclosure are noted in the 61st ASA Program and on the Salon A/B slide scroll.
Mitigating Potential Bias• ACFP:
→ The ACFP’s Sponsorship Guidelines apply to ASA Sponsorship. The ACFP abides by the Canadian Medical Association’s Policy Guidelines for Physicians in Interactions With Industry and the Rx&DAssociation’s Rx&D Code of Ethical Practices. As a non-profit organization, the ACFP complies with Canada Revenue Agency regulations. When deliberating acceptance of sponsorship, the ACFP considers and accepts sponsorship only from those whose products, services, policies and values align with the ACFP vision, values, goals and strategies priorities.
• ASA Planning Committee: → Consideration was given by the 61st ASA Planning Committee to identify when speakers’
personal or professional interests may compete with or have actual, potential or apparent influence over their presentations.
→ Material/Learning Objectives and/or session description were developed and reviewed by a Planning Committee composed of experts/family physicians responsible for overseeing the program’s needs assessment and subsequent content development to ensure accuracy and fair balance.
→ The 61st ASA Planning Committee reviewed Sponsorship Agreements to identify any actual, potential or apparent influence over the program.
→ Information / recommendations in the program are evidence- and/or guidelines-based, and opinions of the independent speakers will be identified as such.
Learning Objectives
• Define symptomtatic hypogonadism and its frequency
• Explore the approach to the diagnosis of Testosterone Deficiency Syndrome (TDS)
• Review all Testosterone Replacement Therapy (TRT) options and appropriate follow –up
• Highlight ongoing controversies regarding the safety of TRT
PRE – NEEDS ASSESSMENT
(it’s all about YOU!!)
1. Treatable hypogonadism MUST be symptomatic and confirmed by (multiple) LOW T readings
2. Use whatever treatment the patient is most comfortable with and always encourage appropriate lifestyle changes – clinical
response takes time
3. If on TRT - monitor q 3monthly for 1st year and annually thereafter (goal: T in therapeutic range and nil else untoward)
4. TRT does NOT cause Prostate Cancer and may be protective for CV events (very low T is associated with higher mortality)
NEW CANADIAN GUIDELINESThe Diagnosis and management of
testosterone deficiency syndrome in men: clinical practice guideline
Multidisciplinary Task Force CMAJ OCT 26 / 2015
Morales et al
Hypogonadism• Characterized by:
– Deficiency in serum testosterone (T) levels ± changes in receptor sensitivity to androgens
• Also known as:– Hypogonadism
– Late-onset hypogonadism (LOH)
– Testosterone Deficiency Syndrome (TDS)• Formerly termed: Andropause
PREVALENCE
Prevalence of TDS
• Crude prevalence rate in Canada:– 25% of men aged 40 to 82 years are biochemically
testosterone deficient1
• Prevalence rates expected to rise with life expectancy (LE)– Over the next 40 years LE in North America will increase
by 4.8 years2
• Yet <10% of affected men receive T therapy3
1. Morley JE, et al. Metabolism. 2000;49:1239-1242.2. United Nations DoEaS, Affairs Population D. World Population Prospects: The 2006 Revision, Highlights;Working Paper
No. ESA/P/WP.202; 2007.3. Carruthers M. Aging Male. 2009;12:21-28.
Prevalence of Hypogonadism in Males Aged at Least 45 Years: The HIM Study
Mulligan T, et al. Int J Clin Pract 2006;60:762-9
Age-specific Prevalence of Hypogonadism
Age (years) Prevalence (%)(95% CI)
45–54 34.0 (30.6–37.4)
55–64 40.2 (36.6–43.8)
65–74 39.9 (35.4–44.4)
75–84 45.5 (39.0–52.1)
85+ 50.0 (32.7–67.3)
Total 38.7 (36.6–40.7)
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Low testosterone high-risk groups
• Type 2 diabetes• Metabolic syndrome• HIV-associated weight loss• Treatment with opioids, glucocorticoids or ketoconazole• Osteoporosis or low trauma fracture at a young age• End-stage renal disease and maintenance hemodialysis• Chronic obstructive pulmonary disease• Infertility• Sellar region mass, disease, radiation or trauma• Use of street drugs• Liver disease
1. Morales et al. CUAJ. 2010;4:269-75.
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Quality of life
1. Novak et al. Maturitas. 2002;43:231-7.
Testosterone deficiency negatively impacts quality of life
Social functioning
Energy
Physical functioning
Socio-emotional functioning
Sexual functioning
Mental functioning
Emotional functioning
Adapted from Novak et al.
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How do I diagnose testosterone deficiency?
1. Morales et al. CUAJ. 2010;4:269-75.
• Subjective testing
• Objective testing
Symptoms of Hypogonadism• Decreased libido• Decreased vitality• Fatigue• Mood changes• Insomnia• Anemia• Delayed ejaculation• Hot flushes• Erectile dysfunction• Decreased muscle mass• Increased visceral body fat• Testicular atrophy• Weakness• Osteopenia/osteoporosis• Loss of facial, axillary and pubic hair
Mild deficiency
Severe deficiency
Morales A. Can Urol Assoc J 2010;4:269-75
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Objective testing
• Serum testosterone measurement– Measure when signs and symptoms of testosterone deficiency are present:
• Low libido• Sexual dysfunction• Low energy
• Testosterone levels are thought to be influenced by circadian rhythm – Higher levels in the morning– Measure between 7 a.m. and 11 a.m.1,2
1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.
Blood–Testosterone Balance
Free T(2%)
Low-affinity proteins(Ka: M3 M-1), such as albumin, transferrin, and transcortin(40–60%)
High-affinity proteins(Ka: M9 M-1), such as SHBG(50–60%)
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Serum testosterone
Alb: albumin; SHBG: sex hormone binding globulin; T: testosterone.1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.
Free(0.5-3%)
Albumin Bound(~38%)
SHBG Bound(~60%)
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Testing recommendations
• Canadian consensus recommends bioavailable testosterone2,3
– Acceptable alternatives:• Calculated free testosterone• Calculated bioavailable testosterone • Total testosterone
1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Morales et al. CUAJ. 2010;4:269-75; 3. Bebb. BCMJ. 2011;53:474-79.
Calculated Free and Bioavailable T
• More accurate reflection of bioactive T• T and DHT circulate in plasma unbound (free approximately 2–
3%), bound to SHBG and weakly bound to albumin• SHBG-bound fraction is biologically inactive because of high
binding affinity for T• Free T = free fraction• Bioavailable T = free T plus T weakly bound to albumin
www.issam.ch/freetesto.htm
SUGGEST using 4.0 as lower CUT-OFF
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Primary VS. Secondary causes
Results in:•Low testosterone levels• Impairment of spermatogenesis•Elevated gonadotropin levels
Results in:•Low testosterone levels• Impairment of spermatogenesis•Low/low-normal gonadotropin levels
Primary causes• Testicular origin
Secondary causes• Pituitary/hypothalamic origin
Low serum testosterone
Exclude:•Klinefelter syndrome
Exclude:•Pituitary neoplasia•Hyperprolactinemia•Hemochromatosis•Obstructive sleep apnea•Genetic disorders associated with
gonadotropin deficiency1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.
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Low end of normal
• Low testosterone requires investigation of:1
– SHBG levels– Serum luteinizing hormone – Follicle-stimulating hormone – Prolactin
• Distinguish between primary and secondary causes
SHBG: sex hormone binding globulin.1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.
If testosterone level is borderline or low, repeat testing is required for confirmation1,2
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Low end of normal
1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59.
Initiate testosterone therapy if the patient is symptomatic, evaluate response
“THERAPEUTIC TRIAL”
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Differential diagnosis
• If testosterone levels are in the normal range, consider other conditions causing fatigue:– Depression– Hypothyroidism– Sexual dysfunction (low libido/ED) from other causes– Cardiovascular disease– Metabolic syndrome– Diabetes– Anemia
ED: erectile dysfunction.
CHEMICAL NAME TRADE NAME DOSE
INJECTABLE
Testosterone cypionate Depo-testosterone cypionate
200–400 mg every 2–4 weeks IDEAL 100mg/week
Testosterone enanthate Delatestryl
200–400 mg every 2–4 weeksIDEAL 100mg/week
Testosterone undecanoate
Nebido (not available in Canada)
1000 mg every 12 weeks
ORAL Testosterone undecanoate Andriol 120–240 mg BID
TRANSDERMAL
Testosterone patch Androderm 2.5–5 mg daily
Testosterone gel AndroGel 5–10 gm daily
Testosterone gel Testim 5–10 gm daily
Testosterone topical solution Axiron 60 mg daily
Morales A. Can Urol Assoc J 2010;4:269-75
Current TRT Formulations
Potential AEs
Tx Modality Time to peak
serum T levels
Efficacy of T delivery Dosing frequency
AEs related to Txmodality
AEs common to all TRTs
INJECTABLE
2-3 days
• High T levels• Serum estradiol
levels may be increased to above normal
• Every 1-2 weeks
Injection site irritation
Reduced HDL
Fluid retention Worsening of
sleep apnea Gynecomastia Increased rate of
development of benign or malignant prostate disease
Increased PSA Increase in RBC Acne Hair loss Weight gain Dizziness Diarrhea Nausea/vomiting Headache
ORAL
4-5 hours
Low to normal T levels
Absorption affected by food
Elevated DHT levels
Large intra- and inter-individual variability
2-4 times a day
GI bloating and irritation
Reduced HDL
TRANSDERMAL
1-2 days
Midrange of normal T levels
Plasma DHT mildly elevated
Daily Local skin irritation Risk of transfer to
partner (gels)
Tenover L. Rev Urol 2003;5(suppl 1):S22–S28
Current TRT Formulations (cont’d)
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Contraindications to Testosterone
AUA: American Urological Association; IPSS: international prostate symptom score; PSA: prostate specific antigen.1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Morales et al. CUAJ. 2010;4:269-75.
Absolute Contraindications• Prostate or breast cancer• Hematocrit >54%
Relative Contraindications• Severe lower urinary tract symptoms (AUA/IPSS score >19)• Prostate nodule• Baseline PSA greater than 4 ng/mL, or PSA >3 ng/mL in men
at high risk of prostate cancer• Uncontrolled congestive heart failure• Myocardial infarction, acute coronary event, unstable
angina, or coronary revascularization procedure in the preceding 6 months
• Untreated severe obstructive sleep apnea
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Prescribing Decisions:PATIENT factors
• Patient Preference:– Mode of delivery– Frequency of administration
• Daily (patch, topical solution, gel, or oral)• Bi-monthly (injectable testosterone cypionate and
testosterone enanthate)
• Cost/Insurance Coverage• (“DOCUMENTED and SYMPTOMATIC
HYPOGONADISM”)
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Symptom improvement
BMD: bone mineral density; MetS: metabolic syndrome.1. Morales et al. CUAJ. 2010;4:269-75.
Duration of Treatment (months)
Enhanced libido
Improved emotional well-being
Increased energy
Reduced ED
Increased strength
Enhanced BMD
Improved cognition
Enhanced cardiovascular strength
Decreased body fat
Improvement in some components of MetS
Sym
ptom
Impr
ovem
ent
0 1263
Monitoring TRT
• CBC- hematocrit, PSA, lipids, testosterone, (HBA1C, ALT, Cr) Q 3monthly for 1st year
• And ANNUALLY thereafter
• DRE is recommended for men >40 years with baseline PSA >0.6 ng/mL who are initiating testosterone
• If PSA becomes abnormal, stop T and consider referral for TRUS/biopsy
Morales A. Can Urol Assoc J 2010;4:269-75
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Changes in blood parameters
• Assess hematocrit levels1
– Testosterone therapy increases red cell mass in a dose-dependent manner2
– If hematocrit >54%, stop therapy until hematocrit decreases to safe levels – Evaluate patient for hypoxia and sleep apnea– Restart therapy — consider different testosterone formulation
• Assess serum testosterone levels1
– Testosterone therapy aims to raise levels to the mid-normal range
1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Coviello et al. J Clin Endocrinol Metab. 2008;93:914-19.
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Adverse Events
• Potential adverse events:1
– Acne, oiliness of skin– Breast tenderness– Erythrocytosis– Growth of metastatic prostate cancer– Detection of subclinical prostate cancer– Reduced sperm production and infertility– Leg edema and worsening of obstructive sleep apnea*
– Gynecomastia*
– Growth of breast cancer*
– Male pattern balding*
*Weak evidence of association.1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70.
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Non-response to treatment
1. Morales et al. CUAJ. 2010;4:269-75.
• Non-compliance• Malabsorption (orally or through skin)• Insufficient dose• Unsatisfactory formulation• Symptoms unrelated to testosterone
deficiency other diagnosis?• Low normal IS NORMAL
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TESTOSTERONE THERAPY IMPROVES SEXUAL FUNCTION
T: testosterone.1. Isidori et al. Clin Endocrinol (Oxf). 2005;63:381-94.
Testosterone therapy results in:
Significant, moderate improvement of all aspects of
sexual function in men with low or low-normal testosterone
levels1
-2 -1 0 1 2 3 4 5 6 All sexual domains (SMD)
Studies with baseline T <10 nmol/L
Sexual Motivation
Erectile Function
Morning Erections
Intercourse
Sexual Satisfaction
Sexual Thoughts
Total Erections
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0.5
0.6
0.7
0.8
0.9
1
0.0 2.0 4.0 6.0 8.0 10.0
Cum
ulat
ive
Surv
ival
Survival (years)
Men with a normal testosterone level (n=452)Men with an equivocal testosterone level (n=240)Men with a low testosterone level (n=166)
Low T and Mortality
Low endogenous testosterone levels are
associated with an increased risk in
mortality
T: testosterone.1. Shores et al. Arch Intern Med. 2006;166:1660-5.
Relationship Between Low Testosterone Levels and Coronary Artery Disease
Multivariate analysis showed increasing severity of CAD with lower testosterone levels.
Rosano GM, et al. Int J Impot Res 2007;19;176-82
8
4
07 14 21
Baseline testosterone, nmol/L
Coro
nary
art
ery
scor
e
n = 129 males, r = -0.52, p < .01
HOT BUTTON CONTROVERSIES
TRUE INCIDENCE ?
“NORMAL AGING”(Clomiphene citrate /HCG)
HOT BUTTON CONTROVERSIES
PROSTATE CANCER
HOT BUTTON CONTROVERSIES
CARDIOVASCULAR DISEASE
• The only two studies to suggest any increase CV risk with testosterone therapyi) TOM Study NEJM July 2010ii) Vigen JAMA. 2013;310(17):1829-1836
• iii) PLOS ONE January 2014 | Volume 9 | Issue 1 • All other previous suggest no effect or decreased risk with testosterone therapy
• European Heart Journal August 2015 - ehv346 DOI:10.1093/eurheartj/ehv346
83,010 men from 1999 – 2104 TRT REDUCED all cause mortality/MI/stroke
• CMAJ – Oct 26 / 2015 Canadian Testosterone Guidelines –Morales et al - use in stable CV disease
http://www.cmaj.ca/content/early/2015/10/26/cmaj.150033
Treatable hypogonadism MUST be symptomatic and confirmed by LOW
Testosterone readings (Testosterone Deficiency Syndrome)
ideally multiple/serial assessments – be a purist (THINK – hypothyroidism)
Use whatever treatment the patient is most comfortable with and encourage appropriate lifestyle changes – clinical
improvements take time
(THINK – obesity/metabolic syndrome) – be a COACH!
If on TRT - monitor q 3monthly for 1st
year and annually thereafter
(goal: T in therapeutic range and nil else untoward)
(THINK diabetes)- be an Accountant
TRT does NOT cause Prostate Cancer and may be protective for CV events
ANDvery low T is associated with higher
mortality
(don’t OVERTHINK) – be an Expert
DISCUSSION
