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How to treat:
TRT Modalities and Formulations
Herman Leliefeld, Urologist / Andrologist
The Netherlands
PRISM Bruges
25-26 June 2015
Brown-Séquard (1817-1894)
Auto-injections with a mixture
of:
-sperm
-testicular tissue
-venous blood
from puppies and Guinea pigs
Lancet,1889,137:105-107
Birth of the Androgen Therapy
Birth of the Androgen Therapy
Eugen Steinach(1861-1944)
- Vasectomy to prevent aging(1918)
To Steinach = to do a Vasectomy =
To Rejuvenate
Birth of the Androgen Therapie
Serge Voronoff(1866-1951)
“treated” 300 patients
“The Monkey Doctor”
Serge Voronoff 1920 Paris
Discovery of androgens in the
1930s
Adolf Butenandt (1903-1995)
in the age of 28y.
Isolation of 15 mg of the first
known androgen:
andro-ster-one from 15000-
25000 liters of policemen’s
urine in 1931
Testosterone-replacement therapy should only be started
in men who have a confirmed diagnosis of
hypogonadism / adult hypogonadism
The goal of treatment is to improve the signs and
symptoms, related to adult hypogonadism: sexual
function, body composition, and quality of life, including
minimizing side effects and optimizing safety and
convenience
Although target testosterone concentrations in serum
might be individualised, generally the aim should be to
achieve those in the mid-normal range provided by a
local laboratory : in practice: not possible
General Remarks:
T is metabolized to 5α-DHT and
17β-Estradiol
Total Testosterone in natural form
either oral or parenteral
Rapid absorption through the portal venous blood
Almost complete metabolisation in the liver before
TT reaches the endorgans
Testosterone
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OHEsterification of 17-hydroxil improves
lipophilicity, enabling parental use
17-alkylation retards hepatic catabolism
1-alkylation retards hepatic catabolism
Testosterone
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OHEsterification of 17-hydroxil improves
lipophilicity, enabling parental use
17-alkylation retards hepatic catabolism
1-alkylation retards hepatic catabolism
Corona et a., Nat Rev Urol. 2010;7:46-56.
Available testosterone
preparations
EAU
Guidelines
March 2015
8 preparations:
Testosterone orallyT. Undecanoate
Disadvantages:
1. Three times daily administration
2. Unpredictable absorption
3. Wide T plasma level fluctuations
Advantages:
1. Easy-to-take (oral)
2. Non toxic (lymph and ductus thoracicus)
3. Wide experience (in Europe)
Breakfast• two rolls
• two slices of cheese
• two slices of ham (20 g)
• butter (20g)
• two cups of caffeine-free coffee
FASTING
Bagchus et al., Pharmacotherapy. 2003; 23:319
Testosterone Undecanoate 2 capsules 40 mg
TestosteroneBuccal T.
Disadvantages:
1. Gel tablet on gums is unpleasant
2. Twice a day application
Advantages:
1. Not expensive?
2. Physiological plasma levels
Testosterone
parenteral
Testosterone by injection
T. Enanthate Short acting
Disadvantages:
1. Wide T plasma level fluctuations
2. Perceived as unpleasant (up and down)
3. Erythrocytosis
Advantages:
1. Injections every 2-3 weeks
2. Cheap
3. Wide experience
Testosterone by injection
T. Propionate very short acting
Disadvantages:1. Multiple injections (2-3 times/week)2. Wide T plasma level fluctuations3. Perceived as unpleasant (up and down)4. Erythrocytosis
Advantages:1. Cheap2. Wide experience
Testosterone by injectionT. Undecanoate in castor oilLong acting
Disadvantages:
1. Pain at injection site
2. Local side effects
3. POME
Advantages:
1. T levels maintained within normal range
2. Long-lasting
3. Less frequent
Long-acting versus Short-acting
baseline 6 18 30
weeks
Zitzmann., Aging Male 9 (Suppl 1):5; 2006
PSA
HTC
PSA
HTC
TT
TRT with testosterone undecanoate in castor oil
Zitzmann., Aging Male 9 (Suppl 1):5; 2006
•Testosterone between 10-15 nmol/l, every 12 weeks
•Testosterone < 10 nmol/l every 10 weeks
•Testosterone > 15 nmol/l every 14 weeks
TRT with testosterone undecanoate in castor oil
Testosterone by patchT. patch
Disadvantages:
1. Itching and contact dermatitis
2. Expensive
3. Easy visibility on body surface
Advantages:
1. Daily application
2. Physiological plasma levels
First line therapeutic approach (gels) & indication
APPROVED by EMA & FDA
Box of 5gr = 30 sachets or dosing pump
Testosterone by gel T. Gel 1%-2%
Disadvantages:
1. Expensive?
2. Potential transfer to women and children
3. Same time every day
Advantages:
1. Daily application on hairless skin
2. Physiological plasma levels
3. Easy to apply
How it works
Apply the gel on the skin
Uptake through the skin
Uptake of the testosterone
in the bloodcirculation
Stable and fysiological T-concentration
Testosterone
nmol/l
Time in
hours
Advantages of the gels
Flexible dose
Predictable bioavailability, constant blood level
Good skin tolerability, no irritation, dry quicly
Available in sachets or pump (easy to apply)
Rapid in T levels (48 hrs) in the presence of adverse events AEs (can be interrupted immediately)
Maintenance of fertility (sperm count)?
Meirelles RMR, Endocrinologia Feminina e Andrologia (Feminine Endocrinology and Andrology), pp.417-428, 2012. Surampudi PN et al., Int J Endocrinol, 2012.: 625434. doi:10.1155/2012/625434Lunenfeld B et al, Aging Health 2009; 5(2) :227-245
In case of fertility wish:
Clomiphene citrate for male hypogonadism
Dose: 3 times a week 50 mg or once a day
Approved only for dysfunction of the ovaries
Selective Estrogen Receptor Modulator(SERM)
Blocking of the feedback inhibition of E2 at the
level of the hypothalamus
Taylor F, J Sex Med 2010;7:269-76
Guay AT, Int J Impot Res 2003;15:156-65
Male Hormone Regulation
Feedback mechanism
blocked by Clomiphene
Only useful if LH and FSH
are low:
hypogonadotropic
hypogonadism
Formulation: Advantages Disadvantages/Side effects
Oral • PO administration • Variable levels of testosterone above and below the mid-range (Irregular bioavailability )
• Variable clinical response• Need for several doses per day
with intake of fatty food.• Risk of hepatotoxicity
Transdermal system • Easy to administer• rapid in T levels in the
presence of adverse events
• Daily administration• Local reactions to application
are common• Can need to administer 2
patches per day
Transbuccal system • Restore T levels in the majority of patients
• Short half-live, requiring change twice a day
• Impossible to adjust the dose• Disagreeable flavor• Mouth Irritation and pain at
the site of application
Meirelles RMR, Endocrinologia Feminina e Andrologia (Feminine Endocrinology and Andrology), pp.417-428, 2012. Surampudi PN et al., Int J Endocrinol, 2012.: 625434. doi:10.1155/2012/625434Lunenfeld B et al, Aging Health 2009; 5(2) :227-245
Therapeutic approach to LOH
Therapeutic approach to LOH
Formulation: Advantages Disadvantages/Side effects
Gel de T 1 – 2% • Flexible dose
• Predictable bioavailability, constant blood level
• Good skin tolerability, no irritation , dry quicly
• Available in sachets or tubes (easy to apply)
• rapid in T levels in the presence of adverse
events AEs (can be interrupted immediately)
• Daily administration
• Risk of transfer by skin contact to women and
children in absence of precaution of use
• Local reactions to applicatio
only significant in case of presence of enhancers
Long lasting injectable • Flexible dose
• Administration of dose every 10 to 14 weeks.
• Pain at injection site (high volume injected)
• High volume of castor oil to be injected• Prolonged↑ in T levels in the presence of AEs• ↑ risk of micro embolism in lung (POME): 30’ FU
after inj
• Long latency time before reaching steady state
Intermediate duration injectable • Low cost
• Flexible dose
• Administration every 2 to 3 weeks
• IM administration
• Pain at injection site
• Peaks and valleys in T levels
• Fluctuations in mood and libido
• Higher occurrence of erythrocytosis in old people
Implants• Treatment every 3 to 6 months
• SC (subcutaneous) surgical insertion
• Pain and inflammation at implant site
• Risk of infection and extrusion of the implants
Meirelles RMR, Endocrinologia Feminina e Andrologia (Feminine Endocrinology and Andrology), pp.417-428, 2012. Surampudi PN et al., Int J Endocrinol, 2012.: 625434. doi:10.1155/2012/625434Lunenfeld B et al, Aging Health 2009; 5(2) :227-245
How to treat: TRT modalities and
Formulations
Herman Leliefeld Urologist /
Andrologist
The Netherlands
PRISM Bruges 25-26 June 2015
Case 61 y ; Vision of family doctor
I send you this patient
Reason: take over treatment
Please your advice
Summary medical file:
Miscommunication with urologist NN
Today’s consultation: June 13th 2014
Needle-phobia; depressive
Loss of libido; small testicles,
Almost no hair;
Recognizes himself in the picture
Case 61 y; Vision first UrologistDear colleague,
Reason consultation: evaluation scrotum,lab
History of the past: mumps orchitis age 18
Medication: none
Allergy: none
Social: afraid of needles in hysterical way
History taken: patient comes with partner
Since 2011 loss of sexdrive; nodule on testicle
Has 2 children in second relation
Phys.Exam.: bilateral moderate atrofic testes
Conclusion: “I don’t see abnormalities of the scrotum;
decline of sexdrive deserves your attention”
Case 61 y, Vision first urologist
Course of action: testosteron,prolaktin,LH, FSH en BPH-lab,
ultrasound scrotum;
Revision later on
Results discussed with partner by telephone on june 11.
Lab: T: 7,8 nmol/l; PSA : 0,7 ug/l
Röntgen: right testicle 3,7 cm ; left testicle 3,4cm
no tumor; normal epididymis
Conclusion: normal testicles.No abnormalities
Conclusion: no urological disturbances
Revision follows if partner wishes so.
What is your first conclusion?
What more do you want to know?
Testosteron Deficiency Syndrome
Lab-results:
Testosterone: 7,8 nmol/l
LH: 41,4 mU / ml
FSH: 64,9 mU / ml
Prolactin: 10,4 ng / ml
Man 62 y; Complaints since 3 years:
-erectile dysfunction
-loss of libido
-no energy
-depressive mood
-sleeping disturbance
-shaving once per 3 days
-smaller testicles since 5 years only
Abdominal
hairlossAtrofic testicles
Conclusion:
Hypergonadotropic Hypogonadism
Testosterondeficiency Syndrome
DD: M.Klinefelter not likely: Fatherhood: 2 daughters
soft not firm testicles
complaints only recently
not a tall man
short legs
karyotype: normal: XY
What is your therapy now?
Therapy
Start Testosterone gel, 50mg per day
Results after 6 weeks:
-Lab: Testosterone from 7,8 to 13,2 nmol/l
Hb:8,4 ; Ht: 40,7
-Complaints: Mood improved
Still ED and no libido yet
What is your next action?
Next action
Increase Testosterone gel to 75 mg per day
Check 6 weeks later : Testosteron:32 nmol/l after 2h
Ht:0,47 ; PSA: 1.4(doubled)
libido now much improved
mood improved
energy improved
sexual intercourse 2 x week
orgasme/ejac. since years!
1
3
6
9
2
457
8
1011
Months
Libido
Vigor
Depression
Red blood count
Obesity
Insulin sensitivity
Erectile function
Bone density
Time-depent and symptom-specific onset of effects of testosterone substitution
Saad, Zitzmann et al. EJE 2011
Conclusion
The urologist missed the case completely
The family doctor was reluctant to send the
patient for a second opinion to second urologist
The patient believed in his own case
Treating these patients is labour-intensive
Mumps-orchitis:seldom sterility, atrophy of the TT
So:
LOH/TDS is still an unknown syndrome!!
How to treat: TRT modalities and
Formulations
Herman Leliefeld Urologist /
Andrologist
The Netherlands
PRISM Bruges 25-26 June 2015