Late Onset Hypogonadism (LOH): Diagnosis & Treatment A.Morales Kingston, Canada.
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Transcript of Late Onset Hypogonadism (LOH): Diagnosis & Treatment A.Morales Kingston, Canada.
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