Late Onset Hypogonadism (LOH): Diagnosis

1
Late Onset Hypogonadism (LOH)Diagnosis
Treatment

• Morales
• Kingston, Canada

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
3
The fantastic years 1890-1920
Xenografts of monkeys testicles
1920
Liquid testiculaire 1896
4
The 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
5
Why 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)

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History Focused Physical
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Defined clinical picture
8
Sensitivity and Specificity of Andropause
Questionnaires
ADAM MMAS AMS
Sensitivity 97 60 83
Specificity 30 59 39
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A 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

10
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 !
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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
8147, 2005
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Diagnostic 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
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A puzzling situation
Confirmed LOH
Testosterone therapy
Monitoring
No/poor response
Endocrine disrupters ?
AR insensitivity ?
Compliance ?
Dose ?
Delivery form ?
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A puzzling situation
Confirmed LOH
Testosterone therapy
Monitoring
No/poor response
Endocrine disrupters ?
AR insensitivity ?
Compliance ?
Dose/IM ?
Delivery form ?
15
But

• Is it only sex hormones ?

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Hormonal alterations with aging

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

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Treatment
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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
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Pharmacological treatment

• General
• Counselling
• Hormones
• Testosterone
• Dehydroepiandrosterone
• Growth hormone
• Melatonin
• Specific
• Biphosphonates
• Antidepressants

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Which preparation ?

• Pills
• Patches
• Injections
• Gels
• Buccal
• Pellets

...and incantations
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Current 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
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Which preparation ?

• Patches
• Pills
• Injections
• Gels
• Lozanges
• Pellets

Efficacy Safety Convenience Availability Price Ele
ctibility
E S C A P E
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They all

• Are safe
• Are effective
• Have slightly different safety and efficacy
  profiles
• Require monitoring

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Monitoring

• Response
• Adverse effects
• Dose adjustments
• Discontinuation of treatment

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Testosterone 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

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Androgen 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

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Postulated 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
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T ? 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
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TE ? 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
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Combination 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
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Study of combination of testosterone and
sildenafil Results erectile function

p 0.029
Shabsigh R. et al. J. Urol 172658 2004
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The logical approach - I
IIEF Domain Score
N 31
35 responded to T alone
Greenstein et al. J Urol 173530, 2005
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The logical approach - II
100 achieve EF domain score gt 26
Greenstein A et al J Urol 173530, 2005
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Monitoring 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
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Monitoring

• Rare AE
• Acne
• Dermatitis
• Gynecomastia
• Fluid retention
• Sleep disturbances

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Monitoring 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
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Are the concerns about HRT applicable to T?
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Are 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

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The 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)
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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

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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 gt 5 years
• US gt 25x106 (now 75x106)
• Bhasin et. al. J. Andrology,
  24299 2003

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Shall 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)

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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

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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

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Thank you