How to treat - prismhealthonline.com · decline of sexdrive deserves your attention ... How to treat: TRT modalities and Formulations Herman Leliefeld Urologist / Andrologist The

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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14 15

1617

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OHEsterification of 17-hydroxil improves

lipophilicity, enabling parental use

17-alkylation retards hepatic catabolism


Testosterone

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OHEsterification of 17-hydroxil improves

lipophilicity, enabling parental use



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


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


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


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


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

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How to treat - prismhealthonline.com · decline of sexdrive deserves your attention ... How to treat: TRT modalities and Formulations Herman Leliefeld Urologist / Andrologist The