Evidences supporting the importance of androgens in male sexuality 1) Castration
2) Hypogonadism
3) Antiandrogen and GnRH analogue Contradictions;
(1 Prepubertal boys
(2 Some castrated males continuing to have intercourse
Testosterone-dependent sexual functions in man
z Sexual desire and arousal z Nocturnal erection z Orgasm and ejaculation z Psychogenic erection; partly
Hirshkowitz M, et al. J Psychosom Res, 1997 5
4 3 2 1
# EPISODES PER NIGHT TOTAL TUMESCENCE TIME (HR)
***
0 MO 3 MO 6 MO 12 MO INFERTILE NORMAL HYPOGONADAL
150 125 100 75 50 25 0
Tip Base
***
*
AUC-RIGIDITY (%std.hr)
Tip Base
Burris AS, et al. J Androl, 1992
Sexual Dysfunction in Partial Androgen Deficiency in Aging Male
Sae-Chul Kim
Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea
Mast + Org Int - Org Int + Org Mast - Org Sexual Events
Pre-Tx Post-Tx INFERTILE NORMAL HYPOGONADAL
NUMBER OF EVENT / WEEK
40
30
20
6
4
2
0
Burris AS, et al. J Androl, 1992
Visually stimulated erection in castrated men with CaP, aged 62-75
Erection yes no
f-T (pg/ml) f-T (pg/ml) Surgically 4 1.22 6 <0.6
(n=10) 0.94
1.25 1.43
Chemically 6 <0.6 (n=6)
Greenstein A, et al. J Urol, 1995
Differences btw primary/secondary and
late-onset hypogonadism
Primary Late-onset
Pathologic Physiologic
Static subnormal T Progressive ↓ to low normal T
Affect all hypogonadal pts Variable btw individual
Tx efficacy; proven Uncertain
Safety assured Risk unknown
남성 성욕감퇴
2 0 .9 3 1 . 4
2 3 . 7 2 6 .4
2 4 . 8 2 2
1 4 . 3 1 7 .1
1 8 .5 2 5 .9
0 5 10 15 20 25 30 35
40-49 50 -59 60-69 70-79 Average age
(%)
Korea Global
Global Survey of Sexual Attitudes and Behavior
Prevalence of Erectile Dysfunction
2 0 .5 31 .4
3 3 .3 4 1 .7
27 .9 2 4. 2
28 . 6
1 7 .8 1 6. 8
1 0 . 7
0 5 10 15 20 25 30 35 40 45
40-49 50-59 60-69 70-79 Average age
(%)
Korea Global
Global Survey of Sexual Attitudes and Behavior
- 7 -
노화에 따른 사정액의 감소
0 10 20 30 40 50 60 70 80
50~54 55~59 60~64 65~69 70~78 백분율
(%)
연령
사정액이 약간 감소 사정액이 심하게 감소 사정불능
• Ref. Blanker MH et al. Urology. 2001;57:763-768.
노화에 따른 사정액의 감소
남성호르몬 결핍증에 의한 남성갱년기 증상 (ADAM 설문지)
1. 성욕감퇴가 있습니까?
2. 기력이 없습니까?
3. 체력이나 지구력에 감퇴가 있습니까?
4. 키가 줄었습니까?
5. 삶의 즐거움이 줄었다고 느낀 적이 있습니까?
6. 울적하거나 기분이 언짢으십니까?
7. 발기가 예전보다 덜 강합니까?
8. 운동경기능력이 최근에 떨어진 것을 느낀 적이 있습니까?
9. 저녁식사 후 바로 잠에 빠져 드십니까?
10. 일의 수행능력이 최근에 떨어졌습니까?
Morley JE, et al (2000). Metabolism, 김수웅 등(2004). 대한비뇨회지
HEALTHY AGING AND MALE SEXUAL FUNCION
♦
77 healthy men, 45-74 years old, recording for 4 nights:
nocturnal erections, serum hormones
♦
Significant inverse correlation between age and:
▶desire, arousal, sexual activity, nocturnal erections
▶bioavailable testosterone but not total testosterone.
♦
Significant correlation between BIO Test. (but non Total T.) and :
▶desire, arousal, nocturnal erections
♦
Most of the correlations with bioavailable testosterone disappear after adjustment for age
Schiavi et al. 1990
Efficacy of AndrodermTMin PADAM (<3.0 ng/ml) with ED; Changes in sexual function
scores (Watts questionnaire)
Domain Baseline 1 mon (n=18) 2 mon (n=17) Desire 16.5 ± 2.85 15.9 ± 3.04 16.8 ± 4.78 Arousal 9.11 ± 2.49 10.1 ± 3.42 10.2 ± 3.93 Orgasm 10.8 ± 3.29 10.9 ± 3.33 11.3 ± 2.49 Satisfaction 7.5 ± 1.42 8.06 ± 1.83 8.65 ± 3.69 Total 43.9 ± 5.5 45.5 ± 7.25 46.8 ± 8.64
Suh KK, et al. Kor J Androl, 1998
Efficacy of AndrodermTMin PADAM (<3.0 ng/ml) with ED;
Improvement of erectile function
Improvement, Number (%) Follow up No Slight Much Total No.
period
1 month 12 (66.7) 5 (27.8) 1 ( 5.6) 18 2 months 11 (64.7) 2 (11.8) 4 (23.5) 17
Suh KK, et al. Kor J Androl, 1998
Changes in number and quality of penile erection, Davidson questionnaire
Baseline 1 month 2 months (N=18) (n=18) (n=17) No. of spontaneous 4.0 ± 3.1 4.8 ± 3.8 4.6 ± 3.2
& morning erection/wk Vaginal intercourse/wk
Had intercourses 14 14 13 Intercourse number 0.91 ± 0.6 1.33 ± 1.1 1.4 ± 1.0 Degree of rigidity
- ~ + (%) 9 (50.0) 4 (22.2) 4 (23.5) ++ (%) 5 (27.8) 8 (44.4) 5 (29.4) +++ (%) 2 (11.1) 4 (23.5) Suh KK, et al. Kor J Androl, 1998
What are reasons for testosterone replacement to be either effective or not
effective to treat ED in PADAM?
The low serum testosterone level may not be the real cause of ED.
▶
One of the many consequences of aging in a multifactorial ED
▶
Consequence of ED rather than its
cause
4.5
1.6
0.3
6.3 5.9
2.7 10.8
8
6.8
10.5 10.5
7.6
0 1 2 3 4 5 6 7 8 9 10 11
<45 45-<65 >=65
Placebo 5 mg 10 mg 20 mg
Is a decline in efficacy of PDE5 inhibitors by age related with a decline in serum T levels by age?
Age Group Week 26 LOCF
Mean Change from Baseline
16 25 22 15 118 114 131 111 36 49 42 57 N
Bayer Study 100249 Efficacy of Vardenafil on EF Domain by Age
100 90 80 70 60 50 40 30 20 10 0
85
65 83
75 77
63
35
16 17 9 15
23 37
56 50
71 80
29 20
24
76 75
25 85
15 63
37 85
15 60
4043
57 50
44
P value <0.001 <0.001 <0.0010.067 0.001 0.024 0.815 1 <0.001 <0.0010.008 0.014 0.003 0.092 0.022 0.754 1 HYP+T HYP-T HTN HTN+DM MM Uncontrolled DM DM+NP A-CAD TOB ASMA PFIB ND PVD ALC TURP PRO (N=108) (N=44) (N=202) (N=43) (N=177) DM (N=18) (N=18) (N=77) (N=55) (N=29) (N=28) (N=20) (N=16) (N=13) (N=10) (N=7)
(N=86)
% failure
% partial success (<50% to 75% of attempts)*
% success (>75% of attempts)
Guay AT et al. J Androl, 2001
AndrogelRalone and in combination with Sildenafil for the treatment of hypogonadal induced ED
• 48 ED patients with hypogonadism (mean age 60. 7 y)
• Androgel therapy alone, 50 mg/ day for 3 months:
Normalizaion of the EFD score (≥26) in 31/48(64%)
• Combination of Sildenafil with Androgel in the 17 non - normalized with Androgel alone:
Normalization of the EFD score in 17/17 Chen KK,et al., 2003 Chen KK,et al., 2003
Uncontrolled Studies Supporting a Beneficial Effect of Testosterone Supplementation in Non-responders to Sildenafil with Low Testosterone
Levels
• Rosenthal et al, 2003: Sildenafil
▶80 ED patients, testosterone < 4ng/ml in 24 (30%)
▶Improved potency in 92% following combination with T gel
• Kalinchenko et al, 2003: Sildenafil
▶120 diabetic ED patients,
mean testosterone; significantly lover than that of responders
▶Marked improvement in 70% following combination with Testosterone undecanoate
6 5 4 3 2
1 0
3 2.5 2 1.5 1 0.5 0
Mean Change From Baseline Mean Change From BaselineMean Change From Baseline
Mean Change From Baseline
0.5
0.4
0.3
0.2
0.1
0 14
12 10 8 6 4 2 0
Week4 week8 week12 Endpoint Week4 week8 week12 Endpoint
Week4 week8 week12 Endpoint Week4 week8 week12 Endpoint Placebo Gel
Testosterone Gel
Erectile function Overall satisfaction
Total score QoL
Shabsigh R, et al. J Urol, 2004
Aversa A, et al. Clin Endocrinol, 2003
Threshold Levels of Plasma Testosterone for its Effect on Sexual Function
■Threshold under which sex function always suboptimal :
▶1.4 ng/ml for nocturnal and psychic erections (Carani 1996)
▶2 ng/ml for sexual activity (Salmimies 1982)
■Threshold above which sexual function always optimal, and non or little stimulated by increasing the level of testosterone :
▶4 ng/ml (supported by numerous studies)
▶However, some stimulating effects of testosterone persist in eugonadal men (> 10 studies)
■Range within which sexual function may be optimal or non- optimal :
▶2 to 4 ng/ml (Salmimies 1982)
Conclusion
Minimal T level may be adequate for a normal erectile response and may be required for a full efficacy of PDE5 Inhibitors.
T may be an effective adjuvant for non- responders to PDE5 inhibitors in PADAM with ED.
Improvement in EF with T replacement in PADAM may be primarily related with central action of T but a local action at penis can not be excluded.
Algorithm for treatment of ED in PADAM
Sexual desire OK, T >2.0 ng/ml;
▶PDE5 inhibitor alone
▶If not effective and T 2-4 ng/ml, T added
↓ Sexual desire, T <2,0 ng/ml;
▶T alone
▶If not effective, PDE5 inhibitor added
Sexual desire OK, T <2.0 ng/ml,
↓ Sexual desire, T 2-4 ng/ml;
▶PDE5 alone
▶If not effective, T added.
