Title: Late Onset Hypogonadism (LOH): Diagnosis
1Late Onset Hypogonadism (LOH)Diagnosis
Treatment
2 A long story The guessing years
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/p
linyepisle.html
3The fantastic years 1890-1920
Xenografts of monkeys testicles
1920
Liquid testiculaire 1896
4The years of discovery 1925-1935
- Laquer E et al.
- isolation of androsterone and testosterone
- Adolf Butenant
- Schering
- Leopold Ružicka
- Organon
- Kàroly Gyula
- Ciba
Nobel Prize for Chemistry, 1939
5Why the healthy skepticism ?
- Clinical manifestations just the infirmities of
old age - It is a life style issue
- Biochemical diagnosis confusing unreliable
- It goes beyond androgen supplementation
- Concerns about treatment safety (prostate, CV,
etc)
6History Focused Physical
7Defined clinical picture
8Sensitivity and Specificity of Andropause
Questionnaires
ADAM MMAS AMS
Sensitivity 97 60 83
Specificity 30 59 39
9A disappointing result CSSAM Questionnaire(CSSAM-
Q)
- Administered by an investigator
- 15 - 20 minutes to complete
- Tested against ADAM and AMS
- All corroborated against a biochemical panel
- CSSAM-Q no better that ADAM or AMS
- Only DHEA-S and GH correlated
10Measuring 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 !
11A 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
8147, 2005
12Diagnostic Algorithm for SLOH
Borderline levels in the presence of symptoms
and/or signs of SLOH without depression
Testosterone therapy trial for 3 months
? A. Morales, 2004
13A puzzling situation
Confirmed LOH
Testosterone therapy
Monitoring
No/poor response
Endocrine disrupters ?
AR insensitivity ?
Compliance ?
Dose ?
Delivery form ?
14A puzzling situation
Confirmed LOH
Testosterone therapy
Monitoring
No/poor response
Endocrine disrupters ?
AR insensitivity ?
Compliance ?
Dose/IM ?
Delivery form ?
15But
- Is it only sex hormones ?
16Hormonal alterations with aging
- ? Sex hormones (T, DHEA, DHEAS)
- ? Growth hormone and IGF-1
- ? Melatonin
- ? Thyroxin
- ? Estradiol
- ? Corticosteroids
- ? Prolactin
- ? Leptin
17Treatment
18Changes 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
19Pharmacological treatment
- General
- Counselling
- Hormones
- Testosterone
- Dehydroepiandrosterone
- Growth hormone
- Melatonin
- Specific
- Biphosphonates
- Antidepressants
20Which preparation ?
- Pills
- Patches
- Injections
- Gels
- Buccal
- Pellets
...and incantations
21Current Formulations
GENERIC 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
22Which preparation ?
- Patches
- Pills
- Injections
- Gels
- Lozanges
- Pellets
Efficacy Safety Convenience Availability Price Ele
ctibility
E S C A P E
23They all
- Are safe
- Are effective
- Have slightly different safety and efficacy
profiles - Require monitoring
24Monitoring
- Response
- Adverse effects
- Dose adjustments
- Discontinuation of treatment
25Testosterone and EF
- The NO system of the CC is dependent on T
- T essential to maintain trabecular smooth muscle
structure and function - Human studies demonstrate benefit of combination
of T and PDE5 inhibitors
26Androgen deficiency
- Promotes differentiation of the stromal precursor
cells of the CC into adipogenic lineage - Accumulation of adiposites in the CC may
contribute to ED - Traish AM, Kim N. Aging Male 8141, 2005
27Postulated Effects of T on Stromal Precursor Cell
Differentiation
Testosterone
5?-reductase
5?-DHT
Stromal Precursor Cell
Fat Cell Lineage
Muscle Cell Lineage
Pre-adiposite progenitor cell
Smooth muscle progenitor cell
Smooth muscle cell
Mature adiposite
Trans-differentiation
?
Traish A, Kim N. Aging Male 8141,2005
28T ? finasteride in older men with hypogonadism
Placebo (n24) T only (n24) T F (n22) P
Age 71 ? 5 71 ? 4 71 ? 4 0.99
BMD ? ? ? lt 0.001
HCRT ? ? ? lt 0.001
Amory JK (Tenover L) JCEM
89503,2004
29TE ? finasteride in older men with hypogonadism
(36 mos.)
Placebo (n24) T only (n24) T F (n22)
Age 71 ? 5 71 ? 4 71 ? 4
Prost. size ? ? ?
PSA ? ? ?
(1.4 ? 1.7)
(1.0 ? 1.4)
(1.4 ? 0.8)
p lt 0.01 compared with baseline p 0.02
compared with placebo and T-only
Amory JK (Tenover L) JCEM
89503,2004
30Combination of T and PDE5Is 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. 2003 2.
Kalinchenko SY et al, Aging Male. 2003 3. Yassin
A et al, Der Mann. 2004
31Study of combination of testosterone and
sildenafil Results erectile function
p 0.029
Shabsigh R. et al. J. Urol 172658 2004
32The logical approach - I
IIEF Domain Score
N 31
35 responded to T alone
Greenstein et al. J Urol 173530, 2005
33The logical approach - II
100 achieve EF domain score gt 26
Greenstein A et al J Urol 173530, 2005
34Monitoring Safety
- Quarterly for the 1st year, yearly thereafter
- Prostate health
- Hematology
- Lipid levels
- Liver function (optional)
- Mood behavior
- Sleep
Morales et al . J.Sex. Med 169 2004
35Monitoring
- Rare AE
- Acne
- Dermatitis
- Gynecomastia
- Fluid retention
- Sleep disturbances
36Monitoring Prostate health
- DRE and PSA
- PSA velocity
- lt 3 years gt 0.4 ngL/yr.
- gt 3 years gt 0.2 ng/L/yr
- PVR
- Uroflow (optional)
- I-IPSS (optional)
- US prostate (very optional)
Risk of Ca P
37Are the concerns about HRT applicable to T?
38Are the concerns about HRT in women applicable to
ART in men ?
- Menopause ADAM conceptually similar
- Large gender differences in response to hormones
- Androgens vs. estrogens and progestins
- (lipolytic, vasodilator vs pro-thrombotic)
- Rotterdam study, JCEM 2002
- Muller M et al. JCEM 885076, 2003
39The age of validation2006-?
- 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)
40Growing 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
41Towards 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 gt 5 years
- US gt 25x106 (now 75x106)
- Bhasin et. al. J. Andrology,
24299 2003
42Shall we put a moratorium on ART?
- I do not think so !
- We need
- Competent physicians managing SLOH/ADAM
- Well informed patients committed to follow-up
- Careful monitoring until larger studies completed
(beyond 2016)
43Conclusions - 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
44Conclusions - 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
45Thank you