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.