Lecture by Prof.Intisar Taibah Universty Androgen |Therapy replacement

1. TESTOSTERONE
REPLACEMENT
THERAPY
INTESSAR SULTAN
52802
8068
MD, MRCP
PROF. OF MEDICINE, TAIBAH U
CONSULTANT ENDOCRINOLOGIST
KFH, MADINAH, 2010

3. TRT: Restoration of
Testosterone to HEALTHY
physiological levels: Sexual
function, mood and bone and
muscle mass.

4. Natural androgens
OH
OH
H
H
H H
H H
O O
H
TESTOSTERONE DIHYDROTESTOSTERONE

7. Testes
Testes & adipose tissues

8. Estrogen action in males
1. Pubertal growth
2. Fusion of epiphysis
3. Maintenance of bone density
4. Gonadotropins regulation

9. INDICATIONS
Hypogonadism
Not osteoporosis or chronic
illness or refractory anemia
Or to build muscles

12. Prevalence of Testosterone
Deficiency

13. ANDROPAUSE
The correct term is 'viropause'
• The end of virility
• Testosterone deficiency
increases with age
• Clinical effects of this
physiological abnormality is
difficult
• More gradual than
menopause, 'hot flushes are
rare.
• Symptoms and signs have
only been associated with
frank hypogonadism (T <
200 ng/dl) (350- 1200
ng/dl).

14. • Current data do not support testosterone
supplementation in healthy, asymptomatic
older men with normal or low–normal
testosterone levels.
• Treatment may be beneficial in older men
with clear hypoandrogenic symptoms,
especially reduced libido, erectile dysfunction
and decreased muscle strength, if testosterone
concentration is consistently low, and the
patient selection, counselling and follow–up
are adequate.

15. DIAGNOSIS

16. SYMPTOMS
SYSTEMIC DZ NOT SD
• Fatigue • Pain/Inflammation
• Loss of muscle • Irritability
mass • Depression
• Fat gain • Decreased memory
• Poor recovery • Loss of Libido
• Erectile Dysfunction

17. Androgen Deficiency in Aging
Males (ADAM) score
1. Do you have a decrease in sex drive?
2. Do you have a lack of energy?
3. Do you have a decrease in strength
and/or endurance?
4. Have you lost height?
5. Have you noticed a decreased enjoyment
of life?

18. ADAM Questionnaire
(con’t)
6.Are you sad and/or grumpy?
7.Are your erections less strong?
8.Has it been more difficult to maintain
your erection throughout sexual
intercourse?
9.Are you falling asleep after dinner?
10. Has your work performance
deteriorated recently?

19. ADAM
• Positive: if pt answers yes:
– To any of the questions pertaining to
sexual disorders or
– To at least three of the other
questions.
• Negative in all other cases
• Sensitive but not specific test

20. INITIAL
HYPOGONADISM
PANEL

21. 1. Total Testosterone
2. Bioavailable/Free T
3. SHBG
4. LH/FSH
5. DHEA-S
6. Estradiol
7. Prolactin

22. 10. Cortisol
11. Thyroid Panel
12. CBC
13. Lipid Panel
14. PSA (if over 40)

23. Measures of testosterone
• Total Testosterone— 300 -1000 ng/dl
sample in the morning on plain tubes.
• Free Testosterone — 2-4%
(80-300 pg/dL)
Equilibrium Dialysis
• Bioavailable Testosterone—Gold
Standard
SHBG
―Free and Loosely/Weakly Bound‖
40-60% (120-600 ng/dL)

24. SHBG
• Obesity (lowering SHBG):
– Lower total testosterone
– Normal free or bioavailable testosterone
• Aging (increasing SHBG):
– Higher total
– Lower bioavailable testosterone.

25. ―Laboratory reference
values for testosterone vary
widely, and are established
without clinical
considerations.‖
Lazarou S, et al. Harvard Medical School, Division of Urology, Beth
Israel Deaconess Medical Center

26. LH/FSH
• LH: primary VS secondary
• FSH: reflect spermatogenesis

27. DHT: ―Evil hormone‖
• 5-AR’d from T so Avoid
AROMATASE INHIBITORS before
testing.
• 25-75 ng/dL
• Serum assay valid?
• Metabolite ratios on 24 hour urines

28. ESTROGEN TESTING
• Total Estrogens is NOT a valid assay
for adult males --cross reactivity w/
progesterone
• Estradiol MUST be by ―ultrasensitive‖
method -ALL OTHERS NOT VALID
• Gold standard is 24 hour urine

29. CONTRAINDICATIONS
TO TRT:
• Prostate CA
• Breast CA
• Untreated prolactinoma

30. RELATIVE
CONTRAINDICATIONS:
• PSA >4.0 or accelerated >0.75
• Hb/Hc> 18/55
• Sleep Apnea
• Cardiac, Hepatic, Renal Dz

31. POTENTIAL RISKS
1. Bladder outlet symptoms due to increase in
prostate volume
2. Stimulation of growth in previously
undiagnosed prostate cancer
3. Edema in patients with preexisting dz
4. Gynecomastia & Weight gain
5. Erythrocytosis (monitor H/H)
6. Precipitation or worsening of sleep apnea
7. Acne
8. Decreased sperm production
9. CVD??: Adverse lipid: LDL, HDL

32. DRUG INTERACTIONS:
• Diabetic Medications
• Propranolol
• Oxyphenbutazone

33. TESTOSTERONE
DELIVERY SYSTEMS

34. TESTOSTERONE
DELIVERY SYSTEMS
• Trans-dermal: consistent, ? adequate
T level, no First-pass effect through
the liver
1. Gels
2. Patches
3. Pellets
4. Buccal
• IM
• Orals: xxxxx

35. Testosterone Gels
• Gel is clear, colorless mixture with
• an alcohol and water base that
• dries quickly after rubbing .
• Applied daily to abdomen, upper arms
or shoulders AM after bathing
Products :
-AndroGel® 5-10 g per day
-Testim™ 5-10 g per day (50 mg
testosterone)

36. Testosterone Gels
Advantages :
Once-a-day dosing
Normalizes testosterone in 24 hrs
Convenient application sites
More potent & Less skin irritation than patches
Disadvantages :
Potential for transfer to partner ?? pregnant or
child
More expensive than other forms of therapy
May elevate ESTROGENS

37. Testosterone Patches:
Androderm®5 mg per day
Use different sites
7 days interval to use same site
Advantage:
•Applied to various areas of the skin as scrotum
•Once-a-day dosing mimics natural cycle
•No risk of accidental transfer
Disadvantage
•Less potency than gels
•2/3’s--Contact Dermatitis
•Higher cost

38. Mean Steady-State Testosterone Concentrations
in Patients Receiving AndroGel®
Day 90
Swerdloff RS, Wang C, Cunningham G, et al. JCEM. 2000;85:4500-4510.

39. Buccal Testosterone
Dose: mucoadhesive table (30 mg) bid
Advantages :
Consistent T level
Disadvantages :
Local irritation
Gingivitis
Bitter taste
BID use

40. Testosterone pellets:
Testopel
•Pellets are slowly released pure T crystals: 100 mg
•Local anesthetic , 6-10 pellets are introduced by a needle
into the fat of the buttock.
•Advantages :
Infrequent dosing, every 3-6 months
Slow rise in T that is maintained over long period
Safe
•Disadvantages :
Requires surgical procedure
Pain and discomfort
Inability to adjust dose easily

41. Testosterone Injections
• Testosterone propionate in oil
• Testosterone enanthate in oil
(Delatestryl)
• Testosterone cypionate in oil (Depotest)

42. Testosterone Injection
• Infrequent dosing, /2-4 wks
• Dramatic physical feeling immediately
after the injection
• The least cost
• Ease of dose titration
• The ―Gold Standard‖ NO MORE!
• Used mainly for men with serious causes
as trauma or cancer.

43. Disadvantages of
testosterone IM:
• Initial levels of testosterone are very high,
may have harmful effects.
• The "roller coaster effect" dosing
irregularities: mood changes, both at the peak
and trough of the dosing cycle.

44. Injection doses
• Testosterone Cypionate IM in oil
(Depotest): 100 mg QW
--double dose ―front load‖
• Glutes: 22 ga 1 ½‖
• Thighs: 25 ga 1‖

45. ORAL PREPARATIONS
• Alkylated to be absorbed and be active.
• First-pass effect through the liver
• Poor serum T levels
• Liver toxicity: cholestasis
• Not recommended for replacement
therapy in long-term situations.

46. FOLLOW-UP LABS
• Total T
• Bio T
• SHBG
• Estradiol : (especially with transdermal)
maintain in mid range
• LH/FSH (especially with transdermal)
• CBC
• Lipid profile
• PSA (if over 40)

47. Initial F/U at 2 weeks with TD
• Stable serum T levels quickly attained
• TD should be applied at same time / day
• Always ask pt. when they apply
• Split dose?
• Allow at least 2 hours s/p application prior
to draw
• 2-4 hours is best with T gels

48. Initial F/U at 6 weeks with IM
• Takes that long to equilibrate
• Cypionate, Enanthate esters peak at
48-72 hours s/p IM injection
• T1/2 = 5-8 days
• No lab draw on injection day

49. FOLLOW-UP LABS
(con’t)
• Once dose is titrated:
--q 6 months or yearly
--Include PSA
--Perform Digital Rectal Exam (DRE)

50. FU: test Estradiol
• Total Estrogens is NOT valid assay
• MUST be monitored during TRT
• Beneficial on lipids and bone BUT Masks
benefits of TRT
• Maintain mid-range (10-50 pg/Ml)
• May rise over time
• TD’s elevate E more than IM

51. Testicular atrophy
nightmare!!!!!!!!

52. • Small doses of HCG are regularly
added to traditional TRT
• Restore the testicles to previous form
and function.
• Stabilizes serum levels
• Rebalance expression of other
hormones
• Increased sense of well-being and
libido.

53. CRISLER HCG PROTOCOL
modified
• -IM: start at 250IU SC two days
immediately previous to IM shot.
-TD: start at 200IU SC every 3rd day
--Never > 500 IU/week (4000 for
fertility): aromatization, elevates
estrogens, progesterone:
gynecomastia
Leydig cell desensitization to LH:
1ry hypogonadism

54. HCG as sole TRT
• Treatment of choice for
hypogonadotrophic hypogonadism
• But it just does not bring the same
subjective benefits as pure testosterone
delivery systems do—even with
similar serum androgen levels

55. Do we have other •
adjunctive for
TRT!!!!!!

56. Tamoxifen: SERM’s
• --Elevates T, but…
--Does not bring subjective benefits of
TRT
• --Cannot assay estrogens on SERM-
class drugs!
• -- Tx for gynocomastia of recent onset
as 3 ms trial before surgery

57. Clomiphene: SERM’s
• -- Racemic mixture (antagonist AND
agonist)
-- May bring untoward visual effects
-- May bring untoward emotional
effects

58. Raloxifen : SERM’s
• --Great estrogen antagonism
--MUCH more expensive

59. DHEA
• -- Effect??
• --25mg BID
--100mg QD can elevate E1

60. Aromatase Inhibitor
• Testolactone 450 mg/d
• Anastrozole 1mg/d
• For gynecomastia ?????
• AI’s as sole TRT is RARE
• Allow 4-5 weeks prior to f/u labs

61. 5 alpha reductase inhibitor
• Men on testosterone replacement
should block the conversion of
testosterone to dihydrotestosterone
(DHT) which affects prostate
hypertrophy and possibly cancer
development.
• Proscar®

62. ANABOLIC STEROIDS
OH OH
CH3 C CH
H H
O N
H H H H
O
O
H
OXANDROLONE (OXANDRIN) DANAZOL (DANOCRINE)
Also classified as 17-alpha alkylated androgens

63. Long
list of
SEs

64. DANAZOLE
• Non aromatizable androgen
• 300 -600 mg/d
• Used in gynecomastia ??
• Weight gain
• Acne

65. Androgenic steroids
Abuse
Young Athletes

67. Superphysiologic doses
• Suppress LH/FSH
• Inhibits spermatogenesis
• Testicular atrophy
• Lower HDL
• Testosterone / epitestosterone < 6

68. Symptoms
• Gynecomastia
• Acne
• Small testicular volume

69. WHAT IS THE FUTURE OF
TRT?
• Elevating T to healthy, happy levels
• Estrogen metabolism
• Actions at the androgen, estrogen
receptors
• Restoring endocrine pathways