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The Role of Testosterone in the Sexual Function
Luiz Otavio Torres
President Elect of ISSM
Belo Horizonte - Brazil
Parassimpatic
Erection
Flacidity
Simpatic ganglia
Spinal cord
MPOA
Paraventricular
Nucleus
Locus
Cerulens
PGN
CC
CE
Erection Center T12
Simpatic and pudendal nerve
Hormones and Sexual Function
Stimuli
visual
tactile
auditive
situational
Testosterone
Sexual Desire
• Melatonine
• Dopamine
• Norepinephrine
• Oxitocine
• NO
• Muscular Trophism
• Vascular Tone
• NO genic expression
(Scientific American .Illustration by John W. Karapelou © 2000)
Cerebralcortex
PRO-ERECTILENEURAL SIGNAL
Testosterone
MPOA
Spinal cord
Testosterone - Erectile Function
Eretogenic stimuli– erotic image– audiovisual– tactile– olfactory
Inibitory stimuli– anxiety– fear– depression
5
+
G -Protein
Guanylatecyclase Adenylatecyclase
Phosphodiesterase 5 Inh.Sildenafil, Tadalafil, Vardenafil, other-
GTP 3´5´-cGMP
5-GMPATP 3´5´-cAMP
O2 + L - Arginine NO + CitrullineeNOS
NANC
nerve
NO VIP
ACH
Dopamine,NO,Oxytocin
Noradrenaline (5HT2C-Rez.)
Serotonin(partly)
alpha-MSH (Melanocortin 2 u. 4 Rez.
Vasopressin,ACTH
+
++
+
+ Parasympathetic
nerves
Stimulatory neurotransmitterSexual Stimulation
++
+
The Impact of Testosterone on Erection
Spinal erection center
S2-S4
Smooth muscle
cell
Endothel+
Testosterone
Testosterone
Testosterone
Testosterone
Actions of Testosterone in Sexual Function
DESIRE
EXCITEMENT
ORGASM
EJACULATION
LEVEL OF
ACTION
LOCAL OF
ACTIONEFFECT
Central
Central
Peripheral
Peripheral
Preoptic
Anterior
Hypothalamic
area
Bulge
Corpora
Cavernosa
Prostate –
Seminal
Vesicles
Libido
Sexual
Drive
Desire
Dysfunction
Nocturnal
erections
Erotic
erections
Ejaculation
Seminal
volume
Erectile
Dysfunction
Ejaculatory/
Orgasmic
Dysfunction
DECREASE
Morales a et al - ICSM 2004 Paris
Testosterone - Endothelial System
-Androgen receptors in the vascular endothelium-Proliferation of smooth muscle and endothelial cels-Modulates the vascular physiology through endothelial dependent and independent mecanisms -Intraluminal injection of T – relaxation of the coronary arteries -Reduce angina and miocardial isquemy induced by physical exercises-Reduce pro-trombotic factors and the development of the ateroma plaque-Low levels of testosterone is associated to the increase of coronary disease and AMI
J Endocrinol 2013;217(3):47-71
Testosterone administration regulates Nitric Oxide syntesis in animal corpora cavernosa
• Morley JE and Perry III HM. Androgen treatment of male hypogonadism in older males. J Steroid Bioch Mol Biology. 2003; 85: 367-73.
• Lugg JA, Rajfer J, Gonzalez-Cadavid NF. Dihydrotestosterone is the active androgen in the maintenance of nitric-oxide mediated penile erection in the rat. Endocrinology. 1995; 136: 1495-501.
• Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M, Orlando C, Vannelli GB, Aversa A, Natali A, Forti G, Jannini EA, Ledda F, Maggi M. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology. 2004; 145: 2253-63.
Testosterone – Erectile Function
Structural changes in the penis -Studies in castrated animals
-Reduction and apoptosis of the smooth muscles of the corpora cavernosa
-Adipocyte accumulation in the sub tunical area
-Decrease of the nervous fibers and mielinic sheets of the cavernous nerves
-Decrease of neuronal and endothelial NOS expression
-Decrease of the smooth muscle relaxation mediated by the NO
-Decrease of the arterial influx to the corpora cavernosa
-Increase of the answer to the alpha-adrenergic vasoconstriction mediators
(Aversa A et al., Eur Urol 2004)
Changes in the rat penile smooth muscles
Castration causes apoptosis T replacement promotes new DNA syntesis
Shabsigh R World J Urol 15: 21-26 (1997)
Effect of Castration and Androgen Substitution on Trabecular Smooth Muscle and Connective Tissue Content in the Corpus cavernosum
Traish A et al. Endocrinol 1999;140(4):1861-1868
Control
Castrated + EstradiolCastrated + Testosterone
Castrated + Vehicle
Traish A et al. Endocrinol 1999;140(4):1861-1868
Changes in the cc smooth muscles and conective tissue in rabbits
Control Lupron 2 weeks. Lupron 8 weeks
Traish A et al. J Androl 24(3): 381-387 (2003)
Shen Z-J Asian J Androl 1: 33-36 (2003)
Group A: Control
rich, regularly arranged elastic fibers
Group B: Castrated (4 weeks)
elastic fibers replaced by collagenous fibers
Effect of Androgen Deprivation on the Ultrastructure of the Tunica albuginea in Rats
Control Castrated
Traish A et al. J Androl 26(2): 88-94 (2005)
Testosterone Modulates the accumulation of adipocyte
In the corpora cavernosa
Withdrawal of testosterone through
castration results in apoptosis of
cavernous smooth muscle cells and
accumulation of adipocytes.
These tissue architecture changes
result in a decrease of cavernosal
compliance with ,in turn, increased
venous outflow and ED.
Traish,A. et al: J Androl. 2005,26,242-248
Sham-operated rabbit
Castrated rabbit
Effect of testosterone deficiency in the cavernous
nerves in rats
Increases Libido
• Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 1992; 75: 1092-98.
• Tan RS, Culberson JW. An integrative review on current evidence of testosterone replacement therapy for the andropause. Maturitas. 2003; 43: 15-27
• Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. 1997; 82: 3793-96
• Jain P, Rademaker AW, McVary KT. Testosterone supplementation for erectile dysfunction: results of a meta-analysis. J Urol. 2000; 164: 371-75.
• Evidences correlates low testosterone and delayed ejaculation
• Low T (< 300 ng/dl)
- 1632 men: 82 with delayed ejaculation
- Controled factors: stress, SSRI, antidopaminergic drugs, prolactin, decreased libido of the patient and partner
Delayed ejaculation and Testosterone
Corona et al J Androl 2008 , Corona `et al JSM 2008; Corona et al Int J Androl 2010
TIMES2 – TRT restores sexual symptoms of Hypogonodism
Another domains at 12 months:
Jones et al Diabetes Care 2011;34:828
Mean changes in the sexual desire domain
• Erectile Function (p=0.089)
• Orgasmic Function (p= 0.176)
• Satisfaction in the intercourse(p= 0.004)
• Sexual satisfaction in general (p= 0.045)
Wang C et al. J Clin Endo Metab 2000; 85:4500-10.
Restores the Sexual Well Being
Desire, erections, sexual activity and satisfaction
1. Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89:2085-2098.