F. Andrew Celigoj1, R. Matthew Coward2, Matthew D. Timberlake1 and Ryan P. Smith1
(1)
Department of Urology, University of Virginia, 800422, Charlottesville, VA 22908, USA
(2)
Department of Urology, University of North Carolina, Chapel Hill, NC, USA
Ryan P. Smith
Email: rps2k@virginia.edu
Keywords
Male sexual functionErectile dysfunctionMale orgasmEjaculatory functionPenile anatomy and physiology
Dr. Coward is a consultant for American Medical Systems and Coloplast
5.1 Introduction
The first known descriptions of penile physiology and erectile dysfunction were described in 2000 BC on Egyptian papyrus. Hippocrates later reported on multiple cases of erectile dysfunction and attributed it to excessive horseback riding. Aristotle hypothesized that the penile erection was facilitated by the influx of air into the penis and that three nerve branches carried spirit and energy to the penis [1, 2]. Leonardo da Vinci observed during the sixteenth century that men undergoing execution by hanging often had reflexogenic erections, on examination finding that a large amount of blood was present within the penis as opposed to air [1, 2]. In a similar fashion, John Hunter made some of the first endeavors to characterize the physiology of ejaculation over 200 years ago. Since that time, ejaculatory dysfunction has become recognized as the most prevalent subclass of male sexual dysfunction [3]. In comparison, the anatomy and physiology of orgasm remain incompletely characterized. Many advances have been made since these classical theorists first proposed the mechanisms behind male sexual function, and the contemporary knowledge of the anatomy and physiology of male sexual function is reviewed in the following text.
5.1.1 Stages of Sexual Response
The human sexual response cycle was first described by Masters and Johnson in 1966 [4] and was later expanded upon by Kaplan [5] and Levin [6]. The sexual response cycle can be described using a four-stage model characterizing the physiologic responses to sexual stimulation: desire, arousal, orgasm, and resolution. Although these occur on a continuum, it is easier to describe them as separate phases. During the desire stage , vascular changes including increased heart rate, blood pressure, and penile tumescence occur. Fluid is secreted from bulbourethral (Cowper’s) and periurethral (Littre’s) glands, lubricating the urethra. The arousal stage continues to the threshold of orgasm. Changes seen during the desire stage are intensified. Breathing, heart rate, and blood pressure continue to increase, and muscle spasms begin in the face, hands, and feet. The orgasm phase is the third and shortest stage. This is the climax of the sexual response cycle characterized by a peak in heart rate, blood pressure, and respiratory rate. This stage is characterized by the emission of seminal fluid, followed by the involuntary muscle contractions of the bulbospongiosus and ischiocavernosus muscles, resulting in ejaculation. This is accompanied by a sudden, euphoric sensation and release of sexual tension. Resolution is the final stage, during which time the physiologic changes observed previously return to their baseline. It is during this stage that penile detumescence occurs, followed by a post-orgasmic refractory period during which recovery is necessary before a male is capable of reaching orgasm again.
5.2 Anatomy and Physiology of Erection
5.2.1 Functional Anatomy of the Penis
The penis is composed of three cylindrical structures: the dorsally paired corpora cavernosa and the ventral corpus spongiosum (Fig. 5.1). The corpora cavernosa are two spongy cylinders separated by a midline, incomplete septum and housed within the tunica albuginea. The bilaminar tunica albuginea surrounds both corpora cavernosa and is a thick envelope composed of organized type I and III collagen interlaced with elastin. The elastic fibers allow for tunical expansion during penile tumescence, while collagen contains and protects the penile spongy erectile tissue, provides rigidity, and participates in the veno-occlusive mechanism through compression of the emissary veins that traverse the tunica albuginea and connect the erectile tissue with the dorsal vein. In contrast, the corpus spongiosum lacks a complete outer layer, ensuring a low-pressure system upon erection and allowing for the expulsion of semen during ejaculation [2, 7]. Within the tunica albuginea is an array of interconnected sinusoids separated by smooth muscle trabeculae with surrounding connective and loose areolar tissue. Each corpus cavernosum is comprised of a complex network of endothelium-lined sinusoids and cavernous smooth muscle, which permit inflow of arterial blood during erection. The fundiform ligament, arising from Colles’ fascia, and the suspensory ligaments, which are derived from Buck’s fascia, provide external penile support. The corpora cavernosa ultimately diverge proximally into the crura of the penis and attach to the ischiopubic rami [2, 7].
Fig. 5.1
Anatomy of the major arteries, veins, and innervation of the penis. Inset: demonstration of the veno-occlusive mechanism. In the flaccid state, there is minimal inflow via the helicine arteries and venous return is abundant. During the erection phase, relaxation of corporal smooth muscle and arterioles increases blood flow. This leads to compression of the subtunical venous plexus by the tunica albuginea (not pictured) limiting the outflow of blood.
5.2.2 Neurovascular Anatomy of the Penis
The primary source of penile arterial blood supply is from the internal pudendal artery, the terminal branch of the anterior trunk of the internal iliac artery. Accessory arteries to the penis may arise from the external iliac, obturator, vesical, and femoral arteries. In some men, these accessory arteries comprise the dominant or solitary vascular supply to the corpora cavernosa [8, 9]. The internal pudendal artery transitions to the common penile artery after giving off a perineal branch. The three branches of the penile artery are the dorsal, bulbourethral, and cavernous arteries, with the dorsal artery being primarily responsible for engorgement of the glans penis during erection. The bulbourethral artery supplies the bulbar urethra and corpus spongiosum and the cavernous artery gives off the many tortuous helicine arteries that supply the trabecular erectile tissue and sinusoids. These helicine arteries are constricted in the flaccid state, but dilate to allow for rapid arterial inflow during erection (Fig. 5.1) [2, 7].
Venous drainage from the corpora cavernosa and the corpus spongiosum parallels the arterial supply, with venous channels intercommunicating variably. Superficial venous drainage is accomplished by multiple subcutaneous veins, which unite to form the superficial dorsal vein and empty into the saphenous veins. Emissary veins, arising from the corpora cavernosa and corpus spongiosum, drain dorsally through the tunica albuginea to the deep dorsal vein, laterally to the circumflex veins, and ventrally to periurethral veins. More proximal emissary veins join to form the cavernous and crural veins [2, 7]. The veno-occlusive mechanism of maintaining blood in the penis during erection relies upon the compression of these tunical emissary veins as the corpora fill and become engorged with blood (Fig. 5.1).
The innervation of the penis is comprised of both autonomic and somatic nerves (Fig. 5.2). Parasympathetic innervation arises from the second, third, and fourth sacral vertebral spinal segments (S2–S4). Preganglionic parasympathetic fibers pass to the pelvic plexus and are joined by sympathetic nerves from the superior hypogastric plexus. The cavernous nerves are branches of the pelvic plexus that innervate the corpora cavernosa and corpus spongiosum and are easily injured during extirpative surgery of the prostate, bladder, and rectum. Sympathetic nervous input to the penis arises from the 11th thoracic through the second lumbar spinal segments and travels through the lumbar splanchnic nerves to the inferior mesenteric and superior hypogastric plexuses. Fibers travel within the hypogastric nerves to the pelvic plexus [2, 10–12]. Stimulation of the pelvic plexus and the cavernous nerves results in erection. In contrast, stimulation of the sympathetic trunk results in detumescence [10, 13].
Fig. 5.2
Neural pathways involved in ejaculation . Sensory input is delivered to the spinal cord via branches of the pudendal nerve. Autonomic nerves are involved with emission of seminal fluid, while motor input to the bulbospongiosus muscles causes expulsion. Spinothalamic nerves are involved with integrating this complex signaling.
Penile sensory pathways originate in the penile skin, urethra, corpora cavernosa, and glans (Fig. 5.2). These nerve endings converge to form bundles of the dorsal nerve of the penis, which later joins with additional cutaneous genital nerves to form the pudendal nerve. The pudendal nerve enters the spinal cord via the S2–S4 nerve roots and terminates in the central gray region of the lumbosacral spinal cord. The pudendal nerve stimulates contraction of the bulbocavernosus and ischiocavernosus muscles, which are essential for the rhythmic propulsion necessary for ejaculation and erectile rigidity, respectively [2, 10–12, 14, 15]. Studies of the dorsal nerve have shown that it maintains both erectile and ejaculatory function via somatic and autonomic components [16]. Supraspinal pathways also provide integration and processing of various afferent inputs (visual, olfactory, genital stimulation) involved in the initiation and maintenance of erection. The medial amygdala, medial preoptic area, paraventricular nucleus, periaqueductal gray, and ventral tegmentum are all associated with sexual function [2, 17–19].
5.2.3 Physiology of Erection
Erection of the penis is a neurovascular event involving sinusoidal relaxation, arterial dilation, and venous compression governed by hormonal and psychological influences. In the flaccid state, the intracorporeal smooth muscle is tonically contracted. This semi-contracted state permits enough arterial flow to allow for nutritional support and is resultant of myogenic activity, adrenergic input, and endothelial factors including prostaglandin F2α and endothelins [2, 20–22]. Upon sexual stimulation, nerve impulses result in the release of neurotransmitters from the cavernous nerve terminals, leading to cavernous, arterial, and arteriolar wall smooth muscle relaxation. Nitric oxide is the principal neurotransmitter regulating penile erection and is released during nonadrenergic, noncholinergic neurotransmission and from the vascular endothelium [7, 23, 24]. Nitric oxide within the smooth muscle activates a soluble guanylyl cyclase, which then raises the intracellular concentration of the second messenger cyclic guanosine monophosphate (cGMP) [16, 23, 25, 26]. The resultant increase in cGMP, via downstream effects on certain proteins and ion channels, leads to a drop in cytosolic free calcium and relaxes the cavernous smooth muscle. Cyclic adenosine monophosphate (cAMP) , like cGMP, represents another intracellular second messenger mediating smooth muscle relaxation. Through activation of specific protein kinases, protein phosphorylation leads to opening of potassium channels, closing of calcium channels, and sequestration of intracellular calcium [2, 7]. Relaxation of the trabecular smooth muscle increases sinusoidal compliance, promoting the tissue filling and expansion [7]. Lue succinctly and accurately summarized the cascade of events that follows: (1) dilation of the arteries and arterioles results in increased diastolic and systolic blood flow within the corpora; (2) sinusoidal expansion results in sequestration of the incoming blood flow; (3) compression of the subtunical venous plexuses between the tunica albuginea and peripheral sinusoids decreases venous outflow; (4) distension of the tunica albuginea to its limiting capacity further decreases venous outflow via occlusion of the emissary veins; (5) subsequent increases in P02 to approximately 90 mmHg and a rise in intracavernosal pressure to approximately 100 mmHg results in elevation of the dependent penis; and (6) contraction of the ischiocavernosus muscles further raises intracavernosal pressure to several hundred millimeters of mercury [2].
Norepinephrine , released from sympathetic nerve terminals, has been accepted as the principal neurotransmitter controlling detumescence. Along with prostaglandin F2α and endothelins, these neurotransmitters activate receptors on smooth muscle cells, leading to a cascade of events translating into increased intracellular calcium concentrations and smooth muscle contraction [2, 20–22]. Detumescence is initiated at the molecular level when cGMP is hydrolyzed to GMP by phosphodiesterases, principally phosphodiesterase type 5, allowing smooth muscle to regain its tone. Coordination of muscle activity through the process of erection and detumescence is facilitated by the presence of gap junctions in the membrane of adjacent muscle cells. These intercellular channels allow the exchange of ions and other second messengers [7, 27, 28].
5.3 Endocrine Influences on Male Sexual Function
The hypothalamic-pituitary-gonadal (HPG) axis plays a critical role in the growth and development of the male reproductive tract and secondary sexual characteristics. For example, testosterone has well-established effects on libido and sexual behavior including sexual interest, frequency of sexual acts, and nocturnal erection [29]. Hypogonadism represents a frequently recognized entity in men who struggle with erectile dysfunction and diminished libido. Indeed, the prevalence of androgen deficiency has been estimated to be 38.7 % in men ≥45 years of age presenting to primary care physicians [30]. The diagnosis of hypogonadism may coincide with associated ailments known to negatively impact sexual function, including the metabolic syndrome, hypertension, type 2 diabetes mellitus, visceral adiposity, insulin resistance, and depression [31, 32].
At a molecular level, androgens promote endothelial cell survival, reduce endothelial expression of pro-inflammatory markers, and inhibit proliferation and intimal migration of vascular smooth muscle cells. Low androgen levels are associated with apoptosis of endothelial cells and smooth muscle cells [2, 33]. Testosterone and dihydrotestosterone may also assist with penile artery and cavernous smooth muscle relaxation [2, 34]. Men on androgen ablation therapy for prostate cancer frequently report poor libido and erectile function. In animal models, castration decreases arterial flow, induces venous leakage, reduces the erectile response to stimulation of the cavernous nerve, and increases the α-adrenergic response of penile smooth muscle [2, 35–38].
Hyperprolactinemia has similarly been associated with reproductive and sexual dysfunction. Elevated prolactin levels inhibit central dopaminergic activity and gonadotropin-releasing hormone secretion, resulting in lower circulating levels of testosterone. This may translate to diminished libido, erectile dysfunction, delayed or inability to achieve orgasm, galactorrhea, gynecomastia, and fertility impairment [2, 39]. Thyroid dysfunction (hyper- and hypothyroidism) may also affect sexual function, as hyperthyroidism has been associated with diminished libido, whereas hypothyroidism results in reduced circulating testosterone and elevated prolactin levels, contributing to erectile dysfunction [2].
5.4 Orgasm and Ejaculation
5.4.1 Anatomy and Physiology of Ejaculation
Antegrade ejaculation is a reflex requiring the complex interaction of somatic, sympathetic, and parasympathetic pathways (Fig. 5.2). It can be separated into two closely timed events: the emission phase and the expulsion phase [40]. Emission occurs due to sympathetic and parasympathetic outflow causing a release of seminal fluid from the prostate, seminal vesicles, and ampullae of the vas deferens into the prostatic urethra, along with closure of the bladder neck [41, 42]. Studies have shown that emission is a result of alpha-adrenergic receptor stimulation by norepinephrine from thoracolumbar sympathetic outflow [43–45]. Disruption of these pathways (i.e., surgical, pharmacological) results in impairment of emission [45].
Following emission, expulsion of seminal fluid from the urethra is due to coordinated contractions of the striated bulbospongiosus and ischiocavernosus muscles while the bladder neck remains closed [41]. The ejaculatory reflex is controlled by motor branches of the pudendal nerve [41] with the cell bodies of these somatic motor neurons being located in the ventral horn of the lumbosacral spinal cord in Onuf’s nucleus [41, 42].
The ejaculatory reflex is controlled by central pattern generators at the spinal level [42]. These central pattern generators, also called lumbar spinothalamic cells , modulate the excitatory and inhibitory supraspinal inputs, which are integrated with sensory input from the dorsal nerve of the penis. These interneurons coordinate the activation of somatic and autonomic spinal centers responsible for ejaculation [46, 47]. Ejaculation is not dependent on supraspinal input, as the majority of men with spinal cord injuries above T10 are able to ejaculate with vibratory or manual stimulation [48, 49].
Supraspinal pathways modulate the ejaculatory reflex. Studies have shown that during ejaculation, the brain centers with the highest activity level include the mesodiencephalic region, the lateral central tegmental field, and the parafascicular nucleus [50]. Stimulation of the medial preoptic area elicits contractions of the bulbocavernosus muscles observed during ejaculation and orgasm [51]. Neurotransmitters play an important role in regulating ejaculation. Studies have shown that activation of serotonin 5HT1A receptors promotes ejaculation, while 5HT1B delays ejaculation [52]. Activation of dopamine receptors D2 and D3 promotes ejaculation [53–56]. Endogenous and exogenous opioids (i.e., tramadol) exhibit an inhibitory effect [57]. The complex interplay between the systems modulates the ejaculatory reflex and serves as a focal point for therapeutic intervention.
5.4.2 Anatomy and Physiology of Male Orgasm
Male orgasm represents a distinct, cortical event that is experienced cognitively and emotionally, and it is mediated through the sensory neurons in the pelvis in response to the striated muscle contractions and expulsion of semen during ejaculation [3]. It may be triggered by genital stimulation, but also by sleep, stimulation of other parts of the body, fantasy, medications, and vibratory stimulation. Orgasm is associated with increased pressure in the posterior urethra, sensory stimuli arising from the verumontanum, and contraction of the urethral bulb and accessory sexual organs [3]. Positron emission tomography studies during orgasm have shown brain activations mainly in the anterior lobe of the cerebellar vermis and deep cerebellar nuclei and deactivations in the left ventromedial and orbitofrontal cortex. While these are similar between genders, in men there is additional activation in the periaqueductal gray matter [58]. Oxytocin levels have been shown to increase in association with orgasm in both genders. Prolactin secretion similarly increases after orgasm and has been proposed as a marker for male orgasm. Oxytocin may contribute to the post-orgasmic refractory period in men whereas prolactin may serve as a neuroendocrine reproductive reflex or as a feedback mechanism modulating dopaminergic systems in the central nervous system [59, 60].
5.5 Summary
The understanding and appreciation of the anatomy and physiology of erection, ejaculation, and orgasm will serve as a cornerstone for the development of new therapies for male sexual dysfunction. Characterization of these pathways and their associated dysfunction remains a critical area of research as exemplified by our limited understanding of orgasm. Until that time, the therapeutic armamentarium available to our patients will be limited by our lack of scientific basis for treatment. A thorough understanding of the anatomy and physiology of these systems is critical to the sexual health practitioner. As captured above, the complex interplay of psychology and physiology in male sexual function necessitates treatment using an integrated approach, combining the benefits of pharmacotherapy, sex and psychotherapy, and surgery.
Acknowledgment
Dr. Celigoj, Dr. Timberlake and Dr. Smith report no conflict of interest.
References
1.
Brenot PH. Male impotence-a historical perspective. Paris: L’Esprit du Temps; 1994.
2.
Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. In: Wein A, Kavoussi LR, Novick AC, Partin AW, Peters CA, editors. Campbell-Walsh urology, vol. 1. 10th ed. Philadelphia: Elsevier Health Sciences; 2011. p. 688–720.
3.
Rowland D, McMahon CG, Abdo C, Chen J, Jannini E, Waldinger MD, et al. Disorders of orgasm and ejaculation in men. J Sex Med. 2010;7(4 Pt 2):1668–86. PubMed PMID: 20388164.CrossRefPubMed
4.
Masters WH, Johnson VE. Reproductive biology research foundation (U.S.). Human sexual response. 1st ed. Boston: Little, Brown; 1966. vol. 8, 366 pp.
5.
Kaplan HS. The new sex therapy; active treatment of sexual dysfunctions. New York: Brunner/Mazel; 1974. vol. 16, 544 pp.
6.
Levin R. An orgasm is…who defines what an orgasm is? Sex Relat Ther. 2004;19:101–7.CrossRef
7.
Lue TF. Erectile dysfunction. N Engl J Med. 2000;342(24):1802–13. PubMed PMID: 10853004.CrossRefPubMed
8.
Breza J, Aboseif SR, Orvis BR, Lue TF, Tanagho EA. Detailed anatomy of penile neurovascular structures: surgical significance. J Urol. 1989;141(2):437–43. PubMed PMID: 2913372.PubMed
9.
Droupy S, Hessel A, Benoit G, Blanchet P, Jardin A, Giuliano F. Assessment of the functional role of accessory pudendal arteries in erection by transrectal color Doppler ultrasound. J Urol. 1999;162(6):1987–91. PubMed PMID: 10569553.CrossRefPubMed
10.
Bella AJ, Brant WO, Lue TF. Microscopic anatomy of erectile function. In: Carson C, Kirby RS, Goldstein IG, Wyllie MG, editors. Textbook of erectile dysfunction. 2nd ed. New York, NY: Informa Healthcare USA, INC; 2009. p. 28–34.
11.
Lue TF, Zeineh SJ, Schmidt RA, Tanagho EA. Neuroanatomy of penile erection: its relevance to iatrogenic impotence. J Urol. 1984;131(2):273–80. PubMed PMID: 6422055.PubMed
12.
Steers WD, Mallory B, de Groat WC. Electrophysiological study of neural activity in penile nerve of the rat. Am J Physiol. 1988;254(6 Pt 2):R989–1000. PubMed PMID: 3381920.PubMed
13.
Giuliano F, Rampin O. Neural control of erection. Physiol Behav. 2004;83(2):189–201. PubMed PMID: 15488539.CrossRefPubMed
14.
Halata Z, Munger BL. The neuroanatomical basis for the protopathic sensibility of the human glans penis. Brain Res. 1986;371(2):205–30. PubMed PMID: 3697758.CrossRefPubMed
15.
McKenna KE. Central control of penile erection. Int J Impot Res. 1998;10 Suppl 1:S25–34. PubMed PMID: 9669218.PubMed
16.
Burnett AL, Tillman SL, Chang TS, Epstein JI, Lowenstein CJ, Bredt DS, et al. Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J Urol. 1993;150(1):73–6. PubMed PMID: 7685426.PubMed
17.
Arnow BA, Desmond JE, Banner LL, Glover GH, Solomon A, Polan ML, et al. Brain activation and sexual arousal in healthy, heterosexual males. Brain. 2002;125(Pt 5):1014–23. PubMed PMID: 11960892.CrossRefPubMed
18.
Mallick HN, Manchanda SK, Kumar VM. Sensory modulation of the medial preoptic area neuronal activity by dorsal penile nerve stimulation in rats. J Urol. 1994;151(3):759–62. PubMed PMID: 8309001.PubMed
19.
Marson L, Platt KB, McKenna KE. Central nervous system innervation of the penis as revealed by the transneuronal transport of pseudorabies virus. Neuroscience. 1993;55(1):263–80. PubMed PMID: 7688882.CrossRefPubMed
20.
Gondre M, Christ GJ. Endothelin-1-induced alterations in phenylephrine-induced contractile responses are largely additive in physiologically diverse rabbit vasculature. J Pharmacol Exp Ther. 1998;286(2):635–42. PubMed PMID: 9694914.PubMed
21.
Italiano G, Calabro A, Spini S, Ragazzi E, Pagano F. Functional response of cavernosal tissue to distension. Urol Res. 1998;26(1):39–44. PubMed PMID: 9537695.CrossRefPubMed
22.
Saenz de Tejada I, Kim N, Lagan I, Krane RJ, Goldstein I. Regulation of adrenergic activity in penile corpus cavernosum. J Urol. 1989;142(4):1117–21. PubMed PMID: 2795742.PubMed
23.
Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun. 1990;170(2):843–50. PubMed PMID: 2166511.CrossRefPubMed
24.
Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med. 1989;320(16):1025–30. PubMed PMID: 2927481.CrossRefPubMed
25.
Pickard RS, Powell PH, Zar MA. The effect of inhibitors of nitric oxide biosynthesis and cyclic GMP formation on nerve-evoked relaxation of human cavernosal smooth muscle. Br J Pharmacol. 1991 104(3):755–9. PubMed Pubmed Central PMCID: 1908248.CrossRefPubMedPubMedCentral
26.
Pickard RS, Powell PH, Zar MA. Nitric oxide and cyclic GMP formation following relaxant nerve stimulation in isolated human corpus cavernosum. Br J Urol. 1995;75(4):516–22. PubMed PMID: 7788263.CrossRefPubMed
27.
Campos de Carvalho AC, Roy C, Moreno AP, Melman A, Hertzberg EL, Christ GJ, et al. Gap junctions formed of connexin43 are found between smooth muscle cells of human corpus cavernosum. J Urol. 1993;149(6):1568–75. PubMed PMID: 8388962.PubMed
28.
Christ GJ, Brink PR, Melman A, Spray DC. The role of gap junctions and ion channels in the modulation of electrical and chemical signals in human corpus cavernosum smooth muscle. Int J Impot Res. 1993;5(2):77–96. PubMed PMID: 7688635.PubMed
29.
Mulligan T, Schmitt B. Testosterone for erectile failure. J Gen Intern Med. 1993;8(9):517–21. PubMed PMID: 8410427.CrossRefPubMed
30.
Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762–9. PubMed Pubmed Central PMCID: 1569444.CrossRefPubMedPubMedCentral
31.
Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases. Int J Androl. 2009;32(6):587–98. PubMed PMID: 19226407.CrossRefPubMed
32.
Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011;8(1):272–83. PubMed PMID: 20807333.CrossRefPubMed
33.
Mirone V, Imbimbo C, Fusco F, Verze P, Creta M, Tajana G. Androgens and morphologic remodeling at penile and cardiovascular levels: a common piece in complicated puzzles? Eur Urol. 2009;56(2):309–16. PubMed PMID: 19147269.CrossRefPubMed
34.
Waldkirch E, Uckert S, Schultheiss D, Geismar U, Bruns C, Scheller F, et al. Non-genomic effects of androgens on isolated human vascular and nonvascular penile erectile tissue. BJU Int. 2008;101(1):71–5. discussion 5. PubMed PMID: 17868421.PubMed
35.
Mills TM, Stopper VS, Wiedmeier VT. Effects of castration and androgen replacement on the hemodynamics of penile erection in the rat. Biol Reprod. 1994;51(2):234–8. PubMed PMID: 7948478.CrossRefPubMed
36.
Penson DF, Ng C, Cai L, Rajfer J, Gonzalez-Cadavid NF. Androgen and pituitary control of penile nitric oxide synthase and erectile function in the rat. Biol Reprod. 1996;55(3):567–74. PubMed PMID: 8862773.CrossRefPubMed
37.
Traish AM, Munarriz R, O’Connell L, Choi S, Kim SW, Kim NN, et al. Effects of medical or surgical castration on erectile function in an animal model. J Androl. 2003;24(3):381–7. PubMed PMID: 12721214.CrossRefPubMed
38.
Traish AM, Park K, Dhir V, Kim NN, Moreland RB, Goldstein I. Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology. 1999;140(4):1861–8. PubMed PMID: 10098525.PubMed
39.
Leonard MP, Nickel CJ, Morales A. Hyperprolactinemia and impotence: why, when and how to investigate. J Urol. 1989;142(4):992–4. PubMed PMID: 2795758.PubMed
40.
Johnson RD. Descending pathways modulating the spinal circuitry for ejaculation: effects of chronic spinal cord injury. Prog Brain Res. 2006;152:415–26. PubMed PMID: 16198717.CrossRefPubMed
41.
Giuliano F, Clement P. Neuroanatomy and physiology of ejaculation. Annu Rev Sex Res. 2005;16:190–216. PubMed PMID: 16913292.PubMed
42.
Giuliano F, Clement P. Physiology of ejaculation: emphasis on serotonergic control. Eur Urol. 2005;48(3):408–17. PubMed PMID: 15996810.CrossRefPubMed
43.
Anton PG, McGrath JC. Further evidence for adrenergic transmission in the human vas deferens. J Physiol. 1977;273(1):45–55. PubMed Pubmed Central PMCID: 1353725.CrossRefPubMedPubMedCentral
44.
Bruschini H, Schmidt RA, Tanagho EA. Studies on the neurophysiology of the vas deferens. Investig Urol. 1977;15(2):112–6. PubMed PMID: 903209.
45.
Kedia K, Markland C. The effect of pharmacological agents on ejaculation. J Urol. 1975;114(4):569–73. PubMed PMID: 1235380.PubMed
46.
Borgdorff AJ, Bernabe J, Denys P, Alexandre L, Giuliano F. Ejaculation elicited by microstimulation of lumbar spinothalamic neurons. Eur Urol. 2008;54(2):449–56. PubMed PMID: 18394782.CrossRefPubMed
47.
Truitt WA, Coolen LM. Identification of a potential ejaculation generator in the spinal cord. Science. 2002;297(5586):1566–9. PubMed PMID: 12202834.CrossRefPubMed
48.
Kafetsoulis A, Brackett NL, Ibrahim E, Attia GR, Lynne CM. Current trends in the treatment of infertility in men with spinal cord injury. Fertil Steril. 2006;86(4):781–9. PubMed PMID: 16963042.CrossRefPubMed
49.
Sonksen J, Biering-Sorensen F, Kristensen JK. Ejaculation induced by penile vibratory stimulation in men with spinal cord injuries. the importance of the vibratory amplitude. Paraplegia. 1994;32(10):651–60. PubMed PMID: 7831070.CrossRefPubMed
50.
Holstege G. Central nervous system control of ejaculation. World J Urol. 2005;23(2):109–14. PubMed PMID: 15875196.CrossRefPubMed
51.
Marson L. Lesions of the periaqueductal gray block the medial preoptic area-induced activation of the urethrogenital reflex in male rats. Neurosci Lett. 2004;367(3):278–82. PubMed PMID: 15337249.CrossRefPubMed
52.
Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis. Int J Impot Res. 2004;16(4):369–81. PubMed PMID: 14961051.CrossRefPubMed
53.
Bitran D, Thompson JT, Hull EM, Sachs BD. Quinelorane (LY163502), a D2 dopamine receptor agonist, facilitates seminal emission, but inhibits penile erection in the rat. Pharmacol Biochem Behav. 1989;34(3):453–8. PubMed PMID: 2533690.CrossRefPubMed
54.
Eaton RC, Markowski VP, Lumley LA, Thompson JT, Moses J, Hull EM. D2 receptors in the paraventricular nucleus regulate genital responses and copulation in male rats. Pharmacol Biochem Behav. 1991;39(1):177–81. PubMed PMID: 1833780.CrossRefPubMed
55.
Ferrari F, Giuliani D. Behavioral effects induced by the dopamine D3 agonist 7-OH-DPAT in sexually-active and -inactive male rats. Neuropharmacology. 1996;35(3):279–84. PubMed PMID: 8783202.CrossRefPubMed
56.
Hull EM, Eaton RC, Markowski VP, Moses J, Lumley LA, Loucks JA. Opposite influence of medial preoptic D1 and D2 receptors on genital reflexes: implications for copulation. Life Sci. 1992;51(22):1705–13. PubMed PMID: 1359367.CrossRefPubMed
57.
Bar-Or D, Salottolo KM, Orlando A, Winkler JV, Tramadol ODTSG. A randomized double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of two doses of the tramadol orally disintegrating tablet for the treatment of premature ejaculation within less than 2 minutes. Eur Urol. 2012;61(4):736–43. PubMed PMID: 21889833.CrossRefPubMed
58.
Georgiadis JR, Reinders AA, Paans AM, Renken R, Kortekaas R. Men versus women on sexual brain function: prominent differences during tactile genital stimulation, but not during orgasm. Hum Brain Mapp. 2009;30(10):3089–101. PubMed PMID: 19219848.CrossRefPubMed
59.
Carmichael MS, Warburton VL, Dixen J, Davidson JM. Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity. Arch Sex Behav. 1994;23(1):59–79. PubMed PMID: 8135652.CrossRefPubMed
60.
Kruger TH, Haake P, Chereath D, Knapp W, Janssen OE, Exton MS, et al. Specificity of the neuroendocrine response to orgasm during sexual arousal in men. J Endocrinol. 2003;177(1):57–64. PubMed PMID: 12697037.CrossRefPubMed