Epididymis

The epididymis is a single, long, convoluted tubule that measures 3 to 4 m in total length, beginning as the caput (head) and continuing as the corpus (body) and tail (cauda). Histologically, once distal to the caput, the epididymal tubule is lined by pseudostratified columnar epithelium of both ciliated and nonciliated types (reviewed by Belleannee and colleagues ). A surrounding network of myoepithelial cells is external to this basal epithelial layer and transitions into smooth muscle cells that are continuous with those of the vas deferens. Neural fibers reside in the peritubular connective tissue and are predominantly sympathetic in origin, being sparse proximally and denser distally. However, estrogen-dependent factors are also important in the basal peristaltic activity within the epididymis, including oxytocin and endothelin-1.

Vas Deferens

The vas deferens measures 25 to 45 cm in length from its origin (transition from) the cauda epididymis to its junction with the seminal vesicle (the confluence of the 2 forms the ejaculatory duct complex). Emerging from the scrotum, the vas enters (external ring) transits and exits (internal ring) the inguinal canal. As it dives down toward the bladder base, heading for its linkage with the ipsilateral seminal vesicles, it spatially separates from the testicular artery and vein. Most of the spermatozoa released during emission are stored within the ampullary region, approximately the last 5 cm. The vasal epithelium is lined by pseudostratified columnar epithelium, which may contain nonmotile stereocilia. The vas deferens has an outer, innervated layer, which supplies the inner trilaminar muscular wall (middle circular sandwiched between outer and inner longitudinal bands). As reviewed by Westfall and Westfall and Burnstock and Verkhratsky, both divisions of the autonomic nervous system innervate the vas deferens; but the sympathetic system has the predominant role. Adrenergic nerve fibers have been found in all 3 muscle layers. Norepinephrine is the primary neurotransmitter, but other putative cotransmitters have been discovered, including vasoactive intestinal polypeptide (VIP), somatostatin, and leu-enkephalin. Nonadrenergic noncholinergic purinergic nerve fibers have also been described in perivasal ganglionic cells.

Seminal Vesicles

The seminal vesicles are lobulated structures that are situated lateral to the ampullary portions of the vas deferens. Each seminal vesicle measures approximately 2 cm in width, 4 cm in length, and 1.5 cm in anteroposterior diameter in the nondilated state. The seminal vesicles contribute 70% of the fluid to each ejaculate (20% from the prostate and 10% from the vasa). The normal semen volume ranges from 1.5 to 5 mL. The pH of the semen is alkaline (range 7.0–8.5). The adventitial lining is rich in blood vessels and terminal neurons. The seminal vesicles contain a very thin single muscle layer. The epithelial lining is pseudostratified columnar in nature and contains a large number of goblet cells. The alveolar arrangement within the seminal vesicles is variable from a single simple duct to a cluster of side ducts and sacs surrounding a short main central duct. Innervation of the seminal vesicles is similar to that of the vasa deferentia via both parasympathetic and sympathetic connections. Recent data have also elucidated nitrergic-mediated signal transduction.

Ejaculatory Ducts

Each ejaculatory duct originates at the junction of the ampullary vas and seminal vesicle and traverses the prostate in an oblique posteroanterior plane to terminate and empty in the prostatic urethra on the verumontanum.

Bladder Neck

The bladder neck serves as a physiologic sphincter during emission and ejaculation. Contraction of the bladder neck, especially during emission, is under sympathetic neural control (alpha-1 adrenergic).

External Urethral Sphincter

The external sphincter belongs to the transverse perineal muscle group and has somatic innervation. The external sphincter surrounds the urethra just distal to the verumontanum.

Perineal Periurethral Muscles

The bulbocavernosus muscle surrounds the corpus spongiosum and urethra and has its origin on the central perineal tendon. There are 3 distinct somatic reflex arcs, from the glans and anterior urethra (the bulbocavernosus reflex) and during ejaculation, all mediated via a branch of the perineal nerve (via the pudendal nerve, S2-4). The ischiocavernosus muscle originates from the ischial tuberosity and has similar innervation to the bulbocavernosus.

Spinal Ejaculation Generator

The ejaculatory reflex center is also referred to as the spinal ejaculation generator , the spinal pacemaker , the central pattern generator , and the spinal pattern generator (as reviewed by Coolen and colleagues ). It is thought to exist at the lower thoracic/upper lumbar level of the spinal cord. It integrates neural input from higher cerebral centers and peripheral sensory afferents with efferent outflow via the sympathetics, parasympathetics, and somatics (vide infra) while also coordinating the temporal sequence of the ejaculatory process. The responsible population of specialized neural cells composing the spinal ejaculation generator has become known as LSt cells (lumbar spinothalamic). It seems that glutamate is the main activating neurotransmitter of N-methyl-d-aspartic acid (NMDA) receptors on LSt cells. Glutamate’s origin may be from the terminus of direct nerve inputs (eg, sensory afferents from the genital skin or from interneurons within and around the LSt cells). Certainly, other neurotransmitters may also influence the activation of the ejaculatory reflex because α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors are expressed in the vicinity of LSt cells and neurokinin1 receptors for substance P are found on LSt cells.

Cortical Input to the Spinal Ejaculation Generator

The exact locations of the cortical foci that both augment and inhibit ejaculation are poorly understood. In a variety of nonhuman species, it has been demonstrated that the spinal ejaculation generator is under both inhibitory and augmentory influence from higher centers. These centers include the medial preoptic area (excitatory, dopaminergic ), the paraventricular nucleus of the hypothalamus (excitatory, oxytocinergic ), and the nucleus paragigantocellularis (inhibitory, serotonergic ). Other areas are also being investigated; but it is known that, absent cortical influence, as occurs in certain spinal cord injuries (SCI), the complete ejaculatory reflex can still be elicited. Input from the cortex arrives to the spinal ejaculation generator via the anterolateral columns of the spinal cord.

Afferent Sensory Input to the Spinal Ejaculation Generator

Sensory input from the penis passes via the afferent nerve fibers of the pudendal nerve to the S2-4 region of the spinal cord. They originate in 2 bundles innervating the penile shaft/glans and the anterior urethra, respectively. Nerve fibers pass from this region of the cord to the spinal ejaculation generator located in the T12-L2 area of the spinal cord. In man, interruption of the afferent nerve fibers from the penis will increase latency of ejaculation but will not result in a loss of the ejaculatory response. These afferent pathways are only one means of relaying sensory input to the emission/ejaculation coordination center. As long as cerebral pathways and sympathetic outflow are intact, ejaculation is possible.

Efferent Sympathetic Output from the Spinal Ejaculation Generator

Sympathetic nerve cell bodies are located in the gray matter lateral columns of the lower thoracolumbar cord, and their axons travel via ventral roots to the paravertebral sympathetic ganglia, most without synapsing, heading toward the superior hypogastric ganglion (also known as the presacral nerve ). Most axons pass through without interruption. The superior hypogastric ganglion overlies the area of the aortic bifurcation at the level of the L4-5 vertebral bodies. These nonsynapsing nerve fibers are components of the hypogastric nerves and terminate in ganglia within the adventitia of the target organs (bladder neck, seminal vesicles, vasa, and prostate). Mauroy and colleagues provided an elegant description of the exact anatomic course and relationships in the pelvis of the inferior hypogastric plexus (pelvic plexus). The resultant postganglionic, nonmyelinated neurons, which innervate the effector organs, are termed the short adrenergics . The long preganglionic nerve fibers use acetylcholine as a neurotransmitter, whereas the short adrenergics use norepinephrine. There may well be crossover in the pelvic plexuses as summarized by Kihara and colleagues. Stimulation via the superior hypogastric ganglion (presacral nerve) induces bladder neck closure and contraction of the muscular elements of the prostate, seminal vesicle, vasa deferentia, and ejaculatory ducts, demonstrating that emission is sympathetically mediated. In terms of the flow of sperm through the epididymis and vas deferens during emission, Kihara and colleagues summarized it as follows: “When the sympathetic signal reaches the cauda epididymis/proximal vas, intraluminal pressure of the cauda epididymis/proximal vas increases and pushes the contents out to the vasal ampulla through the straightened vas deferens, the wall of the ampulla is distended by transported seminal fluid, and both distention and excitation of the nerve elicit efficient contraction to emit the content into the urethra.”

Efferent Somatic Output from the Spinal Ejaculation Generator

Somatic nerve fibers passing from the ventral horn of S2-4, originating in the Onuf nucleus, travel via the perineal branch of the pudendal nerve to supply the bulbocavernosus and ischiocavernosus muscles. Stimulation of this nerve results in clonic contraction of the periurethral muscles forcibly directing the contents of the prostatic urethra in an antegrade direction. The spinal ejaculation generator activates the Onuf nucleus during the proper time and in the appropriate sequence as described later.

RPLND

Surgical removal of the RPLND is an integral part of the overall treatment strategy for testis cancer. It may be used not only for clinical stage 1 and 2 but also when residual masses remain after chemotherapy. The lymph node drainage of the testes is anatomically near and admixed with the tissues containing the thoracolumbar sympathetic outflow as detailed earlier. According to Beck and colleagues, RPLND performed for clinical stage 1, using the present operative strategy, results in postoperative antegrade emission in 97% of patients (99% of those who underwent a nerve-sparing approach and 89% of those who did not). However, Basiri and colleagues reported that of their patients (a similar stage 1 cohort and using the Sloan-Kettering modified template), only 61% had post-RPLND antegrade ejaculation. So, although a great deal of attention is paid to preserve the sympathetics in and around the aorta and its bifurcation, perfect results are not always attainable. Disruption in the neuroanatomy of the ejaculatory response is not secondary to interruption of sacral afferent inflow (sensation from the penis/genitals), to disruption of sacral efferent outflow (motor to the periurethral musculature), or to damage to the spinal ejaculation generator but instead only to the peripheral sympathetic innervation of the vasa, seminal vesicles, prostate, and bladder neck. These men have an orgasmic sensation with sexual stimulation because the cognitive signals from above, the sensory input from below, the spinal ejaculation generator, and the motor outflow are all intact; there is simply no contraction of the vasa, seminal vesicles, and prostate to deliver their contained fluids into the urethra (no emission). Obviously, sympathetic damage may only be partial. Treatment of men with ejaculatory failure after RPLND is described later but, as with all of the conditions described, is easily understood based on knowledge of the normal neuroanatomical and physiologic pathways.

Various Types of Pelvic Surgery

In addition to RPLND, pelvic surgery, such as aortoiliac reconstruction, colorectal excision, and lumbar spine investigation, may also result in ejaculatory dysfunction/failure. For example, up to 63% of male patients undergoing open aortoiliac reconstruction in the past experienced consequent postoperative ejaculatory dysfunction. It is also thought that this is caused by surgical disruption of the many plexuses and nerves immediately in front of the aorta and its bifurcation as well as more inferiorly at the level of the sacral promontory. Using the fact that the superior hypogastric plexus (SHP) is most often slightly left of center, the enveloping tissue, located in the plane anterior to the target vessels, can be incised on the right and then lifted leftward to preserve the delicate neural entanglements as described by van Schaik and colleagues. Likewise, there is a high incidence of ejaculatory dysfunction after low rectal surgery. In a prospective study by Nishizawa and colleagues of 207 men having total mesorectal incision for low rectal cancer, 47% were unable to ejaculate. Lateral lymph node dissection was the strongest risk factor identified. Studies to determine if a laparoscopic approach will be better or worse in preserving both erectile and ejaculatory function postoperatively are underway. An open anterior approach to lumbar spinal surgery is still occasionally used; ejaculatory dysfunction, most often failure of emission, occurred in up to 20% of patients. Lu and colleagues performed an elegant study of the anatomic location of the sympathetic plexuses vis-à-vis where they might be encountered and suggested how to intentionally preserve them during lumbar spinal surgery. It is hoped that this complication will become less common but should not be unanticipated if surgery occurs in this area.

Inguinal Herniorrhaphy

Ejaculatory dysfunction after inguinal herniorrhaphy is unusual, only affecting about 3% to 4% of patients undergoing this procedure, important for fertility in reproductive-aged men. Although the cause is unknown, it is not a direct result of an interruption in the anatomy or neurophysiology of ejaculation. Studies suggest that this may be caused by pain during the sexual act and ejaculation, specifically, secondary to entrapment or inflammation of the vas deferens and inguinal nerves as a response to the mesh used for repairs. Case reports document improvement of dysejaculation following excision of the mesh and transection of the ilioinguinal and iliohypogastric nerves.

Neurologic Illnesses

MS is a demyelinating, T-cell–mediated autoimmune disease that affects the central nervous system at varying levels. Sexual dysfunction may occur in both men and women. Orasanu and colleagues reported an ancillary data analysis of the 2006 North American Research Committee on Multiple Sclerosis (NARCOMS) and determined that 39% of men experienced at least 5 different types of severe symptoms, including too long to achieve orgasm/climax, difficult erection, less intense pleasure with orgasm/climax, lack of interest or desire, and less feeling or numbness in the genitals. Few patients actively sought treatment, and the length of illness was a predictive factor. Similarly, Celik and colleagues had 45 men with MS complete the Multiple Sclerosis Intimacy and Sexuality Questionnaire–19 and the Arizona Sexual Experiences Scale and reported that 37% described some level of sexual dysfunction. Guo and colleagues provide a comprehensive review of the multiple and varied reasons for sexual dysfunction in MS, which may be associated with “anatomic, physiologic, biologic, medical, and psychological factors.” Ejaculatory dysfunction and anorgasmia occur in approximately 50% and 37% of men, respectively. McDougall and McLeod succinctly describe the varied autonomic nervous system abnormalities that may be present. Although not specifically addressing ejaculation, they did find that 50% of men reported erectile difficulties that may impair the ability to ejaculate as a consequence.

Transverse myelitis is a rare disorder involving inflammation of the spinal cord that may span several segments anywhere along its length. Sexual and ejaculatory dysfunction depends on which levels are affected and the residual deficit in function that remained after the resolution.

Neural tube defects may occur at any point along the vertebral column and, even if at the sacral level, will interfere with the neurophysiology of ejaculation. Natural fertility can be seen in those with low cord anomalies, as shown by Laurence and Beresford in 1975, which implies that at least emission was intact and that spermatogenesis was adequate enough to initiate pregnancy. However, Reilly and Oates detailed 10 lumbar level young men, all of whom required electroejaculation (vide infra) and all of whom demonstrated azoospermia in the retrieved semen specimens. On testis biopsy, all had absent spermatogenesis, a completely unexpected finding. So, even though the obvious impediment to their future fertility was the inability to ejaculate that can be overcome with electroejaculation, there also seems to be severe spermatogenic compromise. Hultling and colleagues confirmed poor sperm production capability in men with T12-L4 lesions; the results of Patel and colleagues suggest that this is a problem that begins in infancy, if not before.

Diabetes Mellitus

Autonomic neuropathy (both sympathetics and parasympathetics) and microvascular disease of the reproductive ductal structures are common sequela in longstanding diabetes mellitus and may eventuate in poor or absent emission. Up to 40% of men with diabetes will complain of ejaculatory dysfunction. The vasa deferentia and seminal vesicles may lose their ability to contract as the smooth muscle is replaced by fibrotic, calcified tissue. The spectrum of dysfunction progresses from retrograde ejaculation (intact vasal and seminal vesicle contraction but incomplete, simultaneous bladder neck coaptation) to varying degrees of vasal and seminal vesicle peristaltic failure with reduced/absent sperm quantity and quality in the antegrade or retrograde ejaculate.

Traumatic SCI

Ejaculatory failure is a common consequence of SCI. According to the National Spinal Cord Injury Statistical Center, there are approximately 12,000 new cases of SCI per year and 270,000 people alive with spinal injuries in the United States in 2012 ( www.nscisc.uab.edu ). The average age of injury is 41 years; 80.6% occur in males, and 39% are the result of motor vehicle accidents. These figures may change, however; Schoenfeld and colleagues have reported that “American and coalition forces are sustaining the highest spine combat casualty rates in recorded history and previously unseen injuries are being encountered with increased frequency.” SCI secondary to civilian gunshot wounds makes up approximately 13% to 17% of the total pool of cases of spinal trauma, certainly as important a reason as any and often associated with other comorbid injuries. As reviewed by Brown and colleagues, sexuality and fertility are appropriately major concerns for men after SCI; a team approach, especially regarding the achievement of biologic fatherhood, cannot be overemphasized. Many methods exist to adequately address the issue of erectile dysfunction, which is important to both patients and their partners. The exact nature of the ejaculatory and erectile dysfunction in patients with SCI depends on the level and completeness of the lesion. Considering the level of lesion vis-à-vis the neuroanatomy involved in the human ejaculatory response can generate expectations for residual ability. For example, a complete cervical or high thoracic injury will severe the communication of, and prevent augmentation by, the cortical/cerebral areas above with the spinal ejaculation generator below, even while the remainder of the reflex arc continues on intact. On the opposite end of the spectrum might be an incomplete injury at the sacral level, affecting sensory but not motor. Here, the incoming neural signals from the penile and genital skin may be weaker and less intense than usual on their way into and then up the cord to their destination at the spinal ejaculation generator. If cognitive augmentation is enough of a supplement, the spinal ejaculation generator may reach its critical trigger threshold and initiate the ejaculatory sequence. Forceful expulsion of the seminal fluid bolus may be normal or reduced, depending on the extent of sacral cord motor output disturbance to the periurethral musculature.