hrt and andropause taming the mythical beast€¦ · low end of normal • low testosterone...

HRT and Andropause Taming the

Mythical BeastDr Ted Jablonski MD CCFP FCFP

61st ASA Banff, AB 2016

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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

THANKS !!

dr.t.jablonski@telus.netReferrals / telephone consults

CONTACT:

Monique403-208-3230

FAX 403-208-7310