THE RELEVANCE OF TESTOSTERONE THERAPY IN MANAGING PATIENTS WITH ERECTILE DYSFUNCTION

Transcription

1 THE RELEVANCE OF TESTOSTERONE THERAPY IN MANAGING PATIENTS WITH ERECTILE DYSFUNCTION Aksam A. Yassin MD PhD EdD FEBU Professor of Urology & Human Sexuality Institute of Urology & Andrology, Segeberger Kliniken, Norderstedt Dresden International University, Programm of Men s Health and Preventive Medicine O

2 Sexual activity in relationship to age public opinion age sexual activity Try daily Try weekly Try weakly Try anything 70-? Try to remember

3 Baskin (36.59 %) Ou (66.67 %) Spark (95.45 %) Jacobs (83.33 %) McClure (100 %) Nankin (100 %) Benkert (38.46 %) Carani (42.86 %) Davidson (100 %) Carey (75 %) Ahmed (100 %) Kwan (50 %) Morales (43.48 %) Arver (75.86 %) Skakkebaek (100 %) Conway (100 %) Total (57.02 %) Overall Response Rate to Testosterone Treatment for Erectile Dysfunction in Hypogonadal Men: Results of a Meta-Analysis Jain P et al. J Urol 164: (2000)

4 Where is the Evidence coming Surgical Castration Medical Castration from? Anti-Androgen Treatment 5 Alpha Reductase inhibition NPT studies in hypogonadal men PDE 5 non-responders in hypogonadal men and restoration of response by androgens.

5 History

6 Effects of Castration on Penile Erection in the Cat

7 Effects of Castration on Sexual Function in Man In 12 castrated adult males, sexual potency (power of erection) and libido (sexual desire) were diminished in all castrated patients. McCullagh EP, Renshaw JF. The effects of castration in the adult male. JAMA 1934; 103:

8 Effects of Castration on Sexual Function in Man Lange examined data in 141 soldiers who were castrated due to injury. Sexual potency was immediately obliterated in more than 45% of these patients. Lange, J.: Die Folgen der Entmannung Erwachsener an der Hand der Kriegserfahrungen dargestellt, Arbeit u. Gesundheit, 24: 1-178, 1934.

9 Physiological Factors Influencing Male Erectile Function Neural Vascular Male Erectile Function Endocrine Hormones Structural

10 Three ways to prove T Effects: 1.Androgen Deprivation and its Effects on Erectile Components 2. Data on hypogonadal patients 3. Treatment effects on this group

11 Clinical Studies: Loss of Erectile Function Subsequent Medical Castration Lowering androgen levels with the gonadotropin- releasing hormone (GnRH) agonist leuprolide resulted in the loss of erectile function and sexual activity. Eri LM, Tveter KJ. Safety, side effects and patient acceptance of the luteinizing hormone releasing hormone agonist leuprolide in treatment of benign prostatic hyperplasia. J Urol 1994;152:

12 Clinical Studies: Loss of Erectile Function Subsequent Medical Castration Hirshkowitz et al. investigated the effects of LHRH agonists on 10 healthy, young adult males Subjects taking LH-RH agonist had significant decline in sleep-related erection duration at week 4 and significant reductions at weeks 8 and 12. It took several weeks to notice clinical signs and symptoms of androgen deficiency. Hirshkowitz M, Moore CA, O Connor S, Bellamy M, Cunningham GR. Androgen and sleep-related erections. J Psychosom Res 1997;42:

13 % Stretched Penile Length before and after ADT (3 Injections of Long-Acting GnRHa) plus Subsequent Radiation Therapy for Prostate Cancer 15 before therapy after therapy * : p< * * * * * months (n=47) 0-9 months (n=47) 0-12 months (n=39) 0-15 months (n=35) 0-18 months (n=24) Haliloglu A et al. J Urol 177: (2007)

14 Animal Experiments

15 Penile Anatomy Flaccid Sinusoids Fibromuscular skeleton Venous plexus Tunica Erect (veno-occlusion)

16 Castration Causes Apoptosis in the Rat Penis Replenishment with Testosterone after Castration Causes New DNA Synthesis Shabsigh R World J Urol 15: (1997)

17 Effect of Castration and Androgen Substitution on Trabecular Smooth Muscle and Connective Tissue Content in the Corpus cavernosum Control Castrated + Vehicle Castrated + Testosterone Traish A et al. Endocrinol 140(4): (1999)

18 Dorsal Nerve Control Rogers et al. Int J Impot Res Feb;15(1): Dorsal Nerve Castration he

19 Effect of Testosterone on the Cavernosal Nerve Fibers Control (sham-operated) Castrated testosteronetreated animals Castrated animals Traish et al. Endorinology 2011

20 Effect of Androgen Deprivation on the Ultrastructure of the Tunica albuginea in Rats Group A: Control rich, regularly arranged elastic fibers Group B: Castrated (4 weeks) elastic fibers replaced by collagenous fibers Shen Z-J Asian J Androl 1: (2003)

21 Three ways to prove T Effects: 1.Androgen Deprivation and its Effects on Erectile Components 2. Data on hypogonadal patients 3. Treatment effects on this group

22 Clinical Symptomatology Usual appearance of young men Typical appearance of testosterone deficiency

23 LOH Symptoms Bone mineral density Muscle mass and strength Obesity Libido Erectile function Hematopoiesis Depressed mood Cognitive function General well-being

24 in % Proportion of Co-morbidities in 771 Men with ED All ED Patients (n=771) 50 Elements of the metabolic syndrome Hypogonadism DM Hypertension Dyslipidemia Coronary disease BPH/LUTS There are patients with multiple co-morbidities Yasin et al. J Urol 177(4): 288 (2007)

25 Testosterone Modulates Adipocyte Accumulation in the Penile Corpus Cavernosum Control Castrated Traish A et al. J Androl 26(2): (2005)

26 Veno-occlusive Mechanism in Penile Erection flaccid venous efflux subtunical compartment arterial Influx Tunica Albuginea No firm erection Vascular leakage

27 Patient showing absence of venous leakage evidenced by cavernosography in a severe hypogonadal state with erectile dysfunction at baseline (left) and after 4,5 months administration of testosterone (right) with better penile composition and opacification. Yassin et al. J Sex Med 2006;3:

28 Three ways to prove T Effects: 1.Androgen Deprivation and its Effects on Erectile Components 2. Data on hypogonadal patients 3. Treatment effects on these groups

29 P a t i e n t s w i t h r e s t o r e d E F i n % Patients with a normal erectile function in % at baseline and till endpoint* of therapy with Testosterone (122 hypogonadal ED patients) Baseline, 0/122 pts 12 weeks, 66/122 pts Endpoint*, 71/122 pts Baseline (n=122) Endpoint* (n=71) Erectile Function (maximum of 30) Sexual Desire (maximum of 10) * Mean follow-up of 8 months Yassin et al. World J Urol 24: Nov. (2006)

30 Look for co-morbidities in nonresponders to PDE-5 inhibitors Failure rate of 18 37% to PDE-5 inhibitors: Depending on co-morbidities : Hypogonadism 50% Diabetes mellitus 35% LUTS / BPS 22% Hypertension 23% Dyslipidemia 29% Yassin et al. IJIR Vol. 14, Suppl. 3, 9/2002

31 Testosterone and Erectile Function: ED patients who did not respond to PDE 5 inhibitors alone, experienced significant improvement in erectile function when treated with testosterone and PDE 5 inhibitor. Aversa A, et al. Clin Endocrinol (Oxf ) 2000;53: Aversa A, et al., Clin Endo 2003;58: Shabsigh R, et al., J Urol 004;172: Shabsigh R. J Sex Med 2005;2: Hwang TI-S, et al., Intl. J. Impotence. Res. 2006; 18: Yassin AA et al., J Sex Med 2006;3: Yassin A Saad F Diede H. Andrologia 38:61-68 (2006)

32 Conclusion: 1. The PDE-5 inhibitors were a breakthrough in treatment of ED 2. their action is limited to promotion of relaxation of smooth muscle, no effect on libido 3. many elderly men are testosterone deficient 4. long-standing testosterone deficiency affects anatomical and physiological substrate of erection 5. testosterone replacement alone can often restore erections