Late Onset Hypogonadism (LOH):Diagnosis & Treatment

A. Morales

Kingston, Canada

On the effect of consuming bulls testicles to regain strenghth

Gaius Plinius Secundum

(Pliny the Elder, A.D. 23-79)

Historie of the World

Liber XXIX

Philemon Holland, trans.

1601

http//penelope.uchicago.edu/holland/plinyepisle.html

A long story: The guessing years

The years of discovery: 1925-1935

• Laquer E et al. • isolation of androsterone and testosterone

• Adolf Butenant• Schering

• Leopold Ružička• Organon

• Kàroly Gyula• Ciba

Nobel Prize for Chemistry, 1939

History & Focused Physical

Defined clinical picture

Sensitivity and Specificity of Andropause Questionnaires

ADAM MMAS AMS

Sensitivity

%

97 60 83

Specificity

%

30 59 39

Measuring testosterone

• Total

• Free• Equilibrium dialysis• Centrifugal ultrafiltration• cFT• Analog ligand assay kits

• Bioavailable• Ammonium sulfate precipitation• cBT

• Free androgen index• T/SHBG

http://issam.ch

Talk to your biochemist and ask hard questions !

A sound advice

“… therefore, it is proposed to rely on total testosterone as a first line assay to support the diagnosis…

Tremblay RR, Gagne JM, Aging Male 8:147, 2005

Low T

Comprehensive evaluation

Testosterone therapy *

Monitoring: quarterly for 1 year, yearly after

Confirmed LOH

Screening for possible SLOH

History and physical ( + )

Biochemical evaluation (serum T) in am

Normal

Re-evaluation: seek other causes

referral if necessary

A. Morales, 2004

Borderline levels in the presence of symptoms and/or signs of SLOH without depression

Testosterone therapy trial for 3 months *

Comprehensive hormonal screen Borderline

Response ( – )

* Absence of contraindications

Response ( + )

Continue treatment

Diagnostic Algorithm for SLOH

A puzzling situation

Confirmed LOH

Testosterone therapy

Monitoring

No/poor response

Compliance ? Delivery form ?Dose/IM ?

Endocrine disrupters ?

AR insensitivity ?

But…

Is it only sex hormones ?

Hormonal alterations with aging

Sex hormones (T, DHEA, DHEAS) Growth hormone and IGF-1 Melatonin Thyroxin Estradiol Corticosteroids Prolactin Leptin

Treatment

Changes in life style:

• Easy to determine– Diet, exercise, elimination of bad habits

• Easy to recruit– Great initial enthusiasm

• Difficult to keep– “nothing is happening”

• Difficult to maintain– Large drop out rate

But they must be a prime objective

Pharmacological treatment

• General– Counselling– Hormones

• Testosterone• Dehydroepiandrosterone• Growth hormone• Melatonin

• Specific• Biphosphonates• Antidepressants

Which preparation ?

• Pills

• Patches

• Injections

• Gels

• Buccal

• Pellets

Current FormulationsGENERIC NAME TRADE NAME DOSE

INJECTABLE Testosterone cypionate

Depo-testosterone cypionate

200-400 mg every 2-4 weeks

Testosterone enanthate

Testoviron Depot 200-400 mg every 2-4 weeks

T undecanoate Nebido 1000 mg every 12 weeks

ORAL Testosterone undecanoate

Andriol 120-240 mg daily

TRANSDERMAL

Testosterone patch

Androderm 2.5-5 mg daily

Testosterone gel Androgel 5-10 gm daily

Testosterone gel Testim 5-10 gm daily

BUCCAL Buccal testosterone

Striant 30 mg twice a day

Which preparation ?

• Patches

• Pills

• Injections

• Gels

• Lozanges

• Pellets

E S C A P EE S C A P E

EfficacyEfficacy

SafetySafety

ConvenienceConvenience

AvailabilityAvailability

PricePrice

ElectibilityElectibility

They all:

• Are safe

• Are effective

• Have slightly different safety and efficacy profiles

• Require monitoring

Monitoring

• Response

• Adverse effects

• Dose adjustments

• Discontinuation of treatment

T finasteride in older men with hypogonadismPlacebo

(n=24)

T only

(n=24)

T + F

(n=22)

P

Age 71 5 71 4 71 4 0.99

BMD < 0.001

HCRT < 0.001

Amory JK (Tenover L) JCEM 89:503,2004

TE finasteride in older men with hypogonadism (36 mos.)

Placebo

(n=24)

T only

(n=24)

T + F

(n=22)

Age 71 5 71 4 71 4

Prost. size * * **

PSA *

Amory JK (Tenover L) JCEM 89:503,2004

(1.4 1.7) (1.0 1.4) (1.4 0.8)

* p < 0.01 compared with baseline

** p = 0.02 compared with placebo and T-only

Combination of T and PDE5–Is inhibitors

• Transdermal T improves penile vasodilation and response to sildenafil 1

• Oral testosterone undecanoate reverses ED in diabetics failing sildenafil alone 2

• Combination therapy with testosterone and tadalafil in hypogonadal patients with ED who do not respond to monotherapy 3

1. Aversa A et al, Clin Endocrinol. 20032. Kalinchenko SY et al, Aging Male. 20033. Yassin A et al, Der Mann. 2004

0

1

2

3

4

5

Mea

n c

han

ge

fro

m b

asel

ine

Week 4 Week 8 Week 12 Endpoint

IIEF: Erectile function domain

Placebo + sildenafil

Testosterone +sildenafil

*

*p = 0.029

Study of combination of testosterone and Study of combination of testosterone and sildenafil: sildenafil: Results: erectile functionResults: erectile function

Shabsigh R. et al. J. Urol 172:658; 2004

The logical approach - I

0

5

10

15

20

25

30

SD EF

Baseline

TRT

Greenstein et al. J Urol 173:530, 2005

IIE

F D

omai

n S

core

N = 31

35% responded to T alone

The logical approach - II

0

5

10

15

20

25

30

Erectile Function

Baseline

T alone

Combination

100% achieve EF domain score > 26

Greenstein A et al J Urol 173:530, 2005

Monitoring SafetyQuarterly for the 1st year, yearly thereafter:• Prostate health

• Hematology

• Lipid levels

• Liver function (optional)

• Mood & behavior

• Sleep

Morales et al . J.Sex. Med 1:69: 2004

Monitoring

• Rare AE:• Acne

• Dermatitis

• Gynecomastia

• Fluid retention

• Sleep disturbances

Monitoring – Prostate health

• DRE and PSA• PSA velocity

• < 3 years: > 0.4 ngL/yr.• > 3 years: > 0.2 ng/L/yr

• PVR• Uroflow (optional)• I-IPSS (optional)• US prostate (very optional)

Risk of Ca P

The age of validation:2006-?

The IOM Recommendations• More research is needed

• Conduct small, short-term trials to document efficacy

• Run large, controlled, blind, randomized trials for safety

The final answer by 2015-2020

(maybe)

Growing Use of Testosterone Therapy• Until the safety and efficacy of testosterone therapy in older men is

established, the committee believes that its use is appropriate only for the indications approved by the FDA (the primary indication is the treatment of hypogonadism) and inappropriate for wide-scale use to prevent possible future disease or for enhancing strength or mood in otherwise healthy older males.

• Testosterone Use and Middle-Aged Men:

– A large-scale clinical trial in middle-aged men does not appear to be the logical next step in testosterone therapy research

– Small clinical trials of the benefits of testosterone therapy in middle-aged men could be fielded as additional arms of the efficacy trials

– Other potential approaches • Collect data on age-specific rate of initiation and duration of use of

testosterone therapy

• Incorporate questions about testosterone use into existing large-scale studies of middle-aged men or add measures of testosterone levels as one of the secondary outcome measures to future research efforts

Towards a definitive answer• To detect a 30% difference in CaP incidence

between T and placebo:• A controlled, randomized, double blind study• Hypogonadal (older) men (T naïve?)• n = 6.000 patients• Follow-up: > 5 years• US$ > 25x106 (now 75x106) Bhasin et. al. J. Andrology, 24:299 2003

Conclusions - I

• Diagnosis of LOH requires clinical and (ideally) biochemical manifestations

• Some biochemical latitude is allowed

• The choice of preparation depends on individual preferences

• Modern delivery formulations are safe and effective

Conclusions - II

• Monitoring is fundamental part of treatment

• Recommendations and guidelines are easy to follow

• No place for the uninterested/uninformed

• Many satisfactions, much to learn, plenty of controversy