2009 Funcion Erectil en El Lesionado Medular

REVIEW ARTICLE
Erectile function and male reproduction in men with spinal cord injury: a review
F. Dimitriadis1, K. Karakitsios2, P. Tsounapi1, S. Tsambalas2, D. Loutradis2, N. Kanakas2, N. T. Watanabe1, M. Saito1, I. Miyagawa1 & N. Sokitis2
1 Urology, School of Medicine, Tottori University, Yonago, Tottori, Japan; 2 Urology, School of Medicine, Ionnina University, Ioninna, Greece
Keywords Erectile functioninfertilityspinal cord injurytestis Correspondence Prof. Nikolaos Sokitis, Urology, School of Medicine, Ionnina University, Metavatiko Building, Ionnina, 45500 Greece. Tel.: +30 6944 3634 28; Fax: +30 2651 0970 69; E-mail: akrosinq@hotmail.com Accepted: June 10, 2009
Summary Spinal cord injury (SCI) in men results in defects in erectile function, ejaculatory process and male reproductive potential. There are alterations in the capacity of men with SCI to achieve reexogenic, psychogenic and nocturnal erections. The sexual function in different stages after SCI and the types of erections depend mainly on the completeness of the injury and the level of neurological damage. Furthermore, most of the SCI men demonstrate defects concerning the entrance of semen into the posterior urethra and the expulsion of the semen through the penile urethra and the urethral orice. In addition, SCI men develop defects in the secretory function of the Leydig cells, Sertoli cells and the male accessory genital glands. The overall result is a decreased quality of the semen is recovered either with penile vibratory stimulation (PVS) or with electroejaculation. Nowadays the therapeutic andrological approach of SCI men focuses on achievement of erectile function, recovery of spermatozoa and assisted reproductive technology. The rst line of therapy recommended for infertility in SCI men is collection of semen via PVS with concomitant evaluation of total motile sperm yields for assisted conception which may include intravaginal insemination, intrauterine insemination, or in vitro fertilisation/intracytoplasmic sperm injection. Patients failing PVS may be referred for electroejaculation or surgical sperm retrieval.
Pathophysiology of spinal cord injury/clinical manifestations Spinal cord injury (SCI) is an offence to the spinal cord leading to temporary or permanent changes in its normal motor, sensory or autonomic activities. According to the International Standards for Neurological and Functional Classication of SCI (ASIA, 2000) the disease can be classied into (a) tetraplegia when the injury is located in the cervical region of the spinal cord with concomitant loss of muscle strength in all four extremities and (b) paraplegia when the insult regards the thoracic, lumbar, or sacral segments. Paraplegia may be due to injury of the cauda equina and conus medullaris as well. Spinal cord injury may be caused by different mechanisms such as destruction from direct trauma, compres 2010 Blackwell Verlag GmbH
sion by bone fragments, haematoma, tumour or disk material and ischaemia from damage or impingement on the spinal arteries. The rst clinical presentation of the injury is that of spinal shock referring to a state of transient physiological (rather than anatomical) reex depression of cord function below the level of injury with associated loss of all sensorimotor functions. An initial release of catecholamines leads to increase in blood pressure. This is followed by hypotension (Ko et al., 1999). Moreover, accid paralysis, including the bowel and bladder is observed. These symptoms usually last several hours to days until the reex arcs below the level of the injury begin to function again (Nacimiento & Noth, 1999). Within days or weeks after the injury, patients with SCI overcome the phase of spinal shock and might regain
139
Andrologia 42, 139165
Spinal cord injury
F. Dimitriadis et al.
varied levels of body function. In several cases and especially when the injury is incomplete, the injured person may continue to recover some functioning for many months or even years in rare cases. However, only a very small fraction of individuals sustaining SCIs recover all functioning (White & Likavec, 1999). A different clinical presentation of SCI is the neurogenic shock characterised by the triad of hypotension, bradycardia and hypothermia. It occurs more commonly in injuries above T6 secondary to the disruption of the sympathetic outow from T1L2 and to unopposed vagal tone (Guly et al., 2008). Neurogenic shock causes loss of sympathetic tone which results in decreased vascular resistance and associated vascular dilatation (Guly et al., 2008). Autonomic dysreexia (AD) is another quite critical clinical situation that a patient with SCI may demonstrate. AD is a syndrome of massive unbalanced reex sympathetic discharge resulting in symptoms such as headache, nausea, sweating above the level of injury and severe hypertension which could lead to sequelae such as stroke and death (Teasell et al., 2000). Therefore it represents a medical emergency. Guttmann & Whitteridge (1947) completed a full description of the syndrome. Usually, it is caused when a noxious or nonnoxious stimulus occurs below the level of SCI. This phenomenon occurs after the phase of spinal shock. AD is especially a concern for patients who have an SCI at or above T6. More than 10 000 new cases of SCI occur annually in the USA, 500 in Scandinavia (Hultling et al., 1997), 7000 in Brazil (Utida et al., 2005) and an estimated number of 2,000 cases in the UK (Brinsden et al., 1997). In the USA, there are approximately 300 000 patients with sequelae from SCI. The majority (82%) of the affected patients are males of reproductive age whose sexual function is severely impaired. In women, SCI results in amenorrhea for 612 months after the injury but their pregnancy rates subsequently approach those of the general population (Sipski, 1991). Most of the SCI men are infertile due to a combination of erectile dysfunction, ejaculatory dysfunction and poor semen quality. Moreover, other factors, including associated diseases and medications, may affect sexual function (Larsen & Hejgaard, 1984; Denys et al., 1998). The percentage of male patients who father children with sexual intercourse represents only 1% of the population of men with SCI (Bors et al., 1950). The technological advances in the management of ejaculatory dysfunction have resulted in the recovery of semen samples from the majority of spinal cord injured-men. However, the problem of poor semen quality is largely unsolved. Most men with SCI require some form of medical or technical assistance to father their own children. In this
140
study, we are reviewing the pathophysiology and current management of sexual function and infertility in SCI men.
Impact of neurological damage to the sexual function and fertility in men with SCI Physiology of penile erection and ejaculation Erection The innervation of the human penis is both autonomic (sympathetic and parasympathetic) and somatic (sensory and motor) and consists of three sets of nerves: the pelvic nerves (parasympathetic), the hypogastric nerves (sympathetic) and the pudendal nerves (somatic) (Brown et al., 2006). The sympathetic and parasympathetic nerves merge to form the cavernous nerves which enter the corpora cavernosa and corpus spongiosum playing a crucial role in the development of neurovascular events during penile erection and detumescence. The somatic nerves are primarily responsible for the penile sensation and the contraction of the bulbocavernosus and ischiocavernosus muscles. The parasympathetic pathway for the achievement of erection arises from neurons in the intermediolateral cell columns of the sacral spinal cord segments S2S4 (Brindley, 1982). The preganglionic bres pass in the pelvic nerves to the pelvic plexus where they are joined by the sympathetic nerves from the superior hypogastric plexus. The cavernous nerves are branches of the pelvic plexus that innervate the smooth muscle of blood vessels of erectile tissue or nonerectile tissue (e.g. vas deferens) and they can be easily damaged during any surgical procedures. The hypogastric nerves contain the axons of the sympathetic preganglionic neurons located between the eleventh thoracic and the second lumbar spinal segments (T11L2) (DeGroat & Booth, 1993). This pathway passes via the white rami to the sympathetic chain ganglia. Some bres then travel via the lumbar splanchnic nerves to the inferior mesenteric and superior hypogastric plexuses. From the latter plexi bres travel to the pelvic plexus. Stimulation of the pelvic nerve and the cavernous nerves induces erection (Brindley, 1982) whereas stimulation of the hypogastric nerve or the sympathetic trunk causes detumescence. This clearly suggests that the sacral parasympathetic input is responsible for the penile erection and the thoracolumbar sympathetic pathway is responsible for the detumescence. The somatosensory pathway originates at the sensory receptors in the penile skin, glans, urethra and within the corpus cavernosum. In the human glans penis, there are numerous afferent terminations including free nerve endings and corpuscular receptors with a ratio of 10 : 1. The free nerve endings are derived from thin myelinated and unmyelinated C bres (Halata & Munger, 1986). The
2010 Blackwell Verlag GmbH
Spinal cord injury
nerve bres from the receptors converge to form bundles of the dorsal nerve of the penis which merge with other nerve bres to become the pudendal nerve. Activation of these sensory receptors leads to the transfer and perception of pain, temperature and touch stimuli via the dorsal and pudendal nerves, spinal cord and spinothalamic tract to the thalamus and sensory cortex. The dorsal nerve is a mixed nerve with both somatic and autonomic components which enable it to regulate both erectile and ejaculatory function (Burnett et al., 1993; Carrier et al., 1995). Onufs nucleus in the S2S4 spinal segments is the centre of somatomotor penile innervation. The respective nerve bres travel within the sacral nerves to the pudendal nerve to innervate the ischiocavernosus and bulbocavernosus muscles. Contraction of the ischiocavernosus muscles produces the rigid-erection phase. Rhythmic contraction of the bulbocavernosus muscle is necessary for ejaculation. Erection is produced by dilatation of the arterioles that supply the erectile tissue of the corpora cavernosa. As the erectile tissue lls with blood, the veins that drain the erectile tissue are compressed against the stiff brous envelope of the corpora cavernosa and venous outow decreases. During erection, there is an inhibition of the activity of noradrenergic axons innervating the corpora cavernosa as noradrenaline causes constriction of the arterioles that supply the erectile tissue by acting on alphaadrenergic receptors. Moreover, during erection there is an increased activity of cholinergic axons (Melman & Rehman, 1999). Acetylcholine has been thought to act by inhibiting the release of noradrenaline from noradrenergic axons. Acetylcholine facilitates the release of vasoactive intestinal polypeptide (VIP). VIP is a powerful smooth muscle relaxant. Furthermore, acetylcholine leads to the release of nitric oxide (NO), another powerful smooth muscle relaxant, by the cholinergic nerve bre ends and the endothelial cells. NO binds to smooth muscle receptors of the corpus cavernosum to increase cyclic guanosine monophosphate levels and thus relax smooth muscles (Schultheiss & Stief, 1999). Some investigators have demonstrated acetylcholinesterase positive axons in human cavernosal tissue. In addition, acetylcholine synthesis and release have been demonstrated in the cavernosal tissue (Blanco et al., 1988). However, other authors (Shirai et al., 1973; Lopez & Kollar, 2000) reported no evidence for the presence of acetylcholinesterase in human cavernous tissue. According to a suggestion by Brindley (1988) the sympathetic nerves of the hypogastric plexus may also cause erection when stimulated. On the other hand, Levin & Wein (1980) have shown that infusion of alpha2-adrenergic antagonists causes erections. This may suggest that noradrenalin is, in fact, the main anti-erectile neurotrans 2010 Blackwell Verlag GmbH
mitter. Another group of investigators have found normal levels of noradrenalin in the corpora cavernosa of men with SCI (Melman et al., 1980). Thus, according to Brindley et al. (1986), the sympathetic system appears to have both erectile and anti-erectile actions (particularly the latter action). The regulation of these opposing actions and their integration with the parasympathetic activity is still under investigation (Brown et al., 2006). The above described mechanisms are responsible for the three types of erection: psychogenic, reexogenic and nocturnal. Psychogenic erection is a result of audiovisual-olfactory stimuli or fantasy (Chuang & Steers, 1999). In general, the sensory inputs are processed in higher centre (imaginative inputs in the limbic system, olfactory inputs in the rhinencephalon and visual inputs in the occipital regions) and are integrated in the medial pre-optic and anterior hypothalamic regions and the paraventricular nucleus. Other sensory inputs from the penis arrive to the brain through ascending spinal pathways. Impulses from the brain modulate the spinal erection centres (T11L2 and S2S4) to regulate the erectile process. The reexogenic erection is a tactile-dependent process mediated by a reex arc. The afferent limb is composed of the dorsal nerve of the penis/pudendal nerve. The impulses reach the spinal erection centres and some of them follow the ascending tract resulting in sensory perception. The efferent limb consists of preganglionic axons travelling within the pelvic nerve to the pelvic plexus where ganglion cells send axons to the penis via the cavernous nerve to induce erection (Chuang & Steers, 1999). Nocturnal erections occur mostly during rapideye-movement sleep. The responsible mechanism is currently not fully understood. Ejaculation The complex process of ejaculation involves the coordination of erection, the propulsion of semen and the prevention of retrograde seminal ow. In humans two main phases can be distinguished. During the initial or emission phase, secretions of the accessory glands are blended with the spermatozoa and the resultant mixture is transported with smooth muscle contraction-mediated movement through the internal segments of the male reproductive tract into the urethra. Both sympathetic and parasympathetic divisions of the autonomic nervous system are responsible for the emission phase (Nadelhaft & McKenna, 1987). The second phase of ejaculation or expulsion phase, includes a speedy, emphatic and rhythmic actuation of semen through the penile urethra and out through the external urethral orice. The expulsion of the semen
141
Spinal cord injury
requires the coordinated and rhythmic contraction of the striated perineal muscles, the bulbocavernosus muscle, the ischiocavernosus muscle, and the external urethral sphincter (Johnson, 1988; Holmes et al., 1991; Schmidt & Schmidt, 1993; Yang & Bradley, 1999). In humans, the responsible centre for this second phase is the Onufs nucleus located in the ventral horn of the spinal cord at the S2-level (Schroder, 1985; Beattie et al., 1993). The dorsal nerve of the penis represents the primary sensory input to the pudendal segmental reex circuit and probably to the proposed ejaculatory spinal pattern generator (Johnson, 1988; Johnson & Halata, 1991). It is the most distal portion of the pudendal nerve innervating sensory endings in the penis and prepuce (Johnson, 1988; Johnson & Halata, 1991). It has been demonstrated that penile mechanoreceptors respond to vibratory and tangential surface tactile stimulation (Johnson & Murray, 1992). In addition, they spontaneously respond to blood ow engorging the erectile tissue in the absence of skin stimulation (i.e. as an internal response to stretch) (Johnson, 1988). Moreover, the penile mechanoreceptors increase their tactile sensitivity during erection possibly through autonomic bre modulation of the sensory nerve endings (Johnson, 1988; Johnson & Halata, 1991). Both experimental and clinical studies investigating the function and behaviour of the dorsal nerve have demonstrated that the integrity of the penile sensory axons is essential for triggering ejaculation (Meisel & Sachs, 1994; Wieder et al., 2000). Furthermore, the dorsal nerve of the penis and the pudendal nerve include visceral afferents innervating the urethral mucosa (McKenna & Nadelhaft, 1989) and the erectile tissue of the corpus cavernosum/spongiosum (Johnson, 1988; Johnson & Halata, 1991) along with the mucocutaneous afferents innervating the glans penis and external urethral orice (Johnson & Halata, 1991). Electrical, tactile or chemical activation of the pudendal primary afferents activates a polysynaptic reex discharge of pudendal motoneurons (McKenna & Nadelhaft, 1989; Johnson & Hubscher, 1998) leading to ejaculation-like motor patterns (McKenna et al., 1991; Carro-Juarez et al., 2003) and causes the bulbocavernosus reex in men (Yang & Bradley, 1999). Pathophysiology of autonomic dysfunction in men with SCI affecting sexual function or the ejaculation process Sexual function in different stages after SCI Guttmann (1976) in his classical work has investigated the pathophysiology of the male sexual organs after the occurrence of SCI and he has distinguished three main phases post-SCI: spinal shock, reex return and readjustment.
142
During the rst phase or spinal shock (Fig. 1), there is a complete or almost complete suppression of reex activity below the level of the cord lesion which may last from a few hours to several weeks. Thus the reex penile erection as well as the bulbocavernosal and the scrotal reexes are all abolished or deeply depressed. The ejaculatory function is also abolished. In complete lesions, however, the penis may become enlarged and partially erect. This is the result of a passive feeding of the corpora cavernosa from paralytic vasodilation following the interruption of the vasoconstrictor bres in the anterolateral tracts of the spinal cord (Guttmann, 1976). Pathophysiologically the penile function during the rst phase of SCI is believed to be the result of the sudden interruption of the suprasegmental descending bre systems that keep the spinal motor neurons in a continuous state of subliminal depolarisation and ready to respond (Adams & Victor, 1989). During the second phase of SCI, reex activity and spasticity may appear in the lower extremities, and bladder and bowel function may become reexogenic. In suprasacral lesions the erection reex becomes one of the components of the autonomic functions below the level of injury taking part in the mass response. Tactile stimuli of varying type and intensity including stimulation of the glans and the penis result in erection (Guttmann, 1976). Erection will be associated with a reex contraction of the bulbocavernosus, ischiocavernosus and the transverse perineal muscles. As soon as the summation of the afferent impulses is strong enough to elicit contraction of the seminal vesicles, ejaculation of the seminal vesicular uid through the urethra occurs (Guttmann, 1976). Sexual readjustment is the third phase after an SCI and depends greatly on the particular persons wishes, experience and sexual habits in his life prior to SCI. Moreover, it is also correlated to a great extent on the cooperation and helpfulness of a partner (Guttmann, 1976). Likewise, Siosteen et al. (1990) have shown that sexual readjustment after SCI is closely and positively correlated to the patients willingness to accept the new modus operandi and to experiment with alternative sexual expressions. The patients age at the time of injury is another important factor. The latter investigators have also suggested that physical and social independence and patients high mood level are further positive determinants of sexual adaptation after SCI. The presence of genital sensation is the most wideranging positive predictive factor of male sexual function, whereas an important negative predictor of sexuality is the presence of spasticity (Anderson et al., 2007). However, the major determinants of the degree and type of sexual dysfunction experienced after SCI are the level of
Spinal cord injury
Fig. 1 Erectile function in different phases after SCI. Relevant references (Guttmann, 1976; Szasz, 1986; Adams & Victor, 1989; Siosteen et al., 1990; Chuang & Steers, 1999; McKenna, 1999; Biering-Sorensen & Sonksen, 2001).
lesion and the degree of completeness of the injury (i.e. the degree of retained function of the isolated spinal cord). Thus, as suggested by Brackett et al. (1996b) the sexual dysfunction may occur due to failure of sympathetic outow, failure of parasympathetic output, failure of somatic afferent and efferent neurotransmission and psychological distress stemming from changes in body image and feelings of inadequacy. Types of erection in men with SCI Bors & Comarr (1960) have associated their names with the early studies quantifying sexual dysfunction following SCI. They have demonstrated that the higher the level of the SCI, the more likely the man has the ability for reex but no psychogenic erections. On the other hand, SCI in the sacral region is likely to be associated with psychogenic rather than reexogenic erections. As then recent studies indicated that different types of SCI may produce three different types of erections: reexogenic erections, psychogenic erections and mixed erections (Chapelle et al., 1980; Beretta et al., 1986; Biering-Sorensen & Sonksen, 1992). Reexogenic erection is brought on by cutaneous or mucous membrane stimulation, and therefore demands a nondamaged reex arc (which includes the S2S4 spinal segments). For lesions above the level of T11 we may expect rigidity of the penis (Biering-Sorensen & Sonksen,
2001). In fact, SCI above the sacral level will not only preserve the erectile reex but can even enhance it, especially if the lesion is complete (Chuang & Steers, 1999). This is the result of the abolished tonic inhibition which controls this reex. The loss of tonic inhibitory control leads to a decreased sensory threshold for achievement of erection (McKenna, 1999). Thus, clinically, men with cervical injuries may expect reex erections as responses to nonsexual touch stimulation associated with situations such as catheterisation or bothering from dressing. These spontaneous erections are produced by the same touching-related mechanism that results in erections during touching by the female partner. Alternatively, if the sacral spinal cord is injured, or if the pudendal nerve or the pelvic nerve is destroyed, then the ability of the SCI men to have reex erections will be lost (Chuang & Steers, 1999). The presence of the bulbocavernosus reex demonstrates an intact sacral reex (McKenna, 1999) determining in this way the future potential for reex erections (Szasz, 1986). Psychogenic erections occur in men with an intact nervous system in response to various stimuli including visual, auditory, or olfactory ones. In addition, a psychogenic erection occurs as a result of dreams, memories and fantasies (Chuang & Steers, 1999). In SCI men with lesions at the sacral level or below psychogenic erections are mediated via the thoracolumbar sympathetic outow
143
Spinal cord injury
(Chuang & Steers, 1999). However, psychogenic erections result only in swelling and lengthening of the penis without rigidity and therefore often occur without the possibility of intromission. Mixed erections may occur when the level of the lesion is below L2 and above S2. The erectile responses may differ individually regarding their duration and quality. It has been suggested that the spontaneous erections are probably caused by covert intrinsic reex stimulation in individuals with upper motor neuron lesions (Comarr, 1970). In summary, an erection in men with SCI is more likely to occur in incomplete than complete lesions. Patients with SCI above the sacral segments probably maintain an intact parasympathetic centre and thus they have a higher frequency of erections than individuals with lower lesions (Grifth et al., 1973). However, this fact is not always correlated to the future sexuality of a particular patient (Comarr, 1970). In fact some investigators have shown that the degree and the neurological level of the damage in the spinal cord have no signicant correlation with the sexual function (Siosteen et al., 1990). Other investigators (Tsuji et al., 1961) have observed in patients with either complete or incomplete SCI, a recovery of erectile function in about 25% of the men within 1 month post-injury. A recovery of erectile function in 60% of the SCI men within 6 months and a recovery of the erectile function in 80% of the SCI men within one year have been demonstrated (Tsuji et al., 1961). In 5% of the SCI men, the erectile function recovery occurred two years after the injury (Tsuji et al., 1961). In patients with cervical or thoracic vertebral injury, 3040% of the men regained erectile function within one month postSCI. In addition, 7080% of the SCI men obtained erectile function within 6 months post-SCI. Only 10% of the men with a lumbar vertebral injury recovered erectile function within 1 month and 40% of these men obtained erectile function within 6 months (Tsuji et al., 1961). Even though many SCI men can have erections, these may not be of sufcient rigidity or duration for intercourse. Ejaculation in men with SCI Ejaculation and orgasm in men with SCI present an even greater controversial issue. In a large-scale study, only 12 15% of a population of men with all types of SCI were able to ejaculate (Donohue & Gebhard, 1995). As it has been above described, the ejaculatory reex, consisting of seminal emission (sympathetic reex) and ejaculation (parasympathetic and somatic reex) can be interrupted by SCI. The most common problem is the absence of ejaculation or the failure of triggering the ejaculatory reex. Unlike reex erections, the triggering of ejaculation
144
in a man with complete upper motor neuron injury requires a specic stimulus and usually a sexual stimulus alone is not adequate. Penile vibrostimulation increases the chance of ejaculation if the thoracolumbar reexes are intact, but again, the vibrator needs to be specically calibrated for the response to occur (Sonksen et al., 1994). Bors & Comarr (1960) have shown that ejaculation in men with complete upper motor neuron lesions is rare. Men with lower motor neuron lesions rarely have erections or ejaculate. The less complete the lesion, the more likely is the man to have reex and psychogenic erections and ejaculate. However, some men feel pain and develop spasms during sexual activity (Slot et al., 1989). Autonomic dysfunction in men with spinal cord injury and fertility Hypothalamicpituitarytesticular axis in men with SCI Normal spermatogenesis is dependent upon an intact hypothalamicpituitarytesticular axis (HPT axis). The effects of SCI on this axis have not yet been claried. Reports on the hormonal proles of SCI men have been conicting. Low, normal or elevated testosterone (Wang et al., 1992), normal or high follicle-stimulating hormone (FSH) and luteinising hormone (LH) (Kikuchi et al., 1976; Wang et al., 1992; Celik et al., 2007), normal or high prolactin (PRL) (Huang et al., 1993), and low T3 hormone and/or T4 hormone (Prakash et al., 1980) levels have been reported. The prevalence of HPT axis abnormalities in spinal cord injured men is high and although the responsible mechanism is not yet clear, it appears that an altered central neurotransmitter activity is present (Naderi & Safarinejad, 2003) and could account for them. Brackett et al. (1994a) reported no signicant differences in serum PRL levels between SCI men and a population of noninjured infertile men. In addition, in the above study peripheral serum testosterone levels were signicantly larger in SCI men than in noninjured infertile men. There were no signicant correlations between the levels of each of these hormones and the semen quality. However, SCI men with elevated FSH levels were azoospermic. It appears that although systemic endocrine changes may accompany SCI, they may not represent the only explanation for the decreased semen quality. Using a rat model, Huang et al. (1995), have shown that in the acute phase of SCI there is a suppression of pituitary-testis hormonal axis which is associated with early changes in spermatogenesis. After this phase, there has been a constant regression of spermatogenesis in 70% of the animals until the third month post-injury. On the other hand, serum FSH, LH and testosterone levels recovered until the rst month post-injury. By the sixth month post-injury, spermatogenesis recovered in nine of the 19
Spinal cord injury
animals (with some persisting abnormalities). An exogenous testosterone regimen failed to prevent such alterations in spermatogenesis (Huang et al., 1998). This observation additionally tends to suggest that nonendocrine factors are involved in the mechanism mediating the effects of SCI on spermatogenesis (Huang et al., 1998). Leydig cell function in men with spinal cord injury The ratio of testosterone to LH has been used as a more sensitive indicator of Leydig cell function than testosterone or LH alone (Giagulli & Vermeulen, 1988; Brennemann et al., 1997). When this ratio was evaluated in SCI men, a statistically signicant decrease was revealed in a patient subpopulation that demonstrated abnormal testicular biopsies compared with the subpopulation of patients with normal biopsies (Elliott et al., 2000). There was no signicant difference in serum FSH, LH, or total testosterone levels between the subpopulation of SCI men with normal biopsy images and the subpopulation of SCI men with abnormal biopsies (Elliott et al., 2000). Huang et al. (1995) have demonstrated an acute phaseeffect of SCI on the pituitary testicular hormone axis in rats. However, in the T9- SCI rat model, there are normal serum levels of FSH, LH and testosterone, and normal intratesticular testosterone concentrations after the 14th day post-injury. The administration of FSH alone or in combination with testosterone signicantly increases the intratesticular and serum testosterone concentrations in acute phase SCI rats (Ottenweller et al., 2000). This effect is not seen in control rats (Ottenweller et al., 2000). These ndings demonstrate that hormonal regulation of both Sertoli and Leydig cells are altered during the acute phase of SCI (Ottenweller et al., 2000). Such alterations in hormonal regulation may modify the functions of both cellular populations, thereby affecting the endocrine and/ or paracrine biochemical microenvironment within the seminiferous tubuli. In summary, the overall result may be a defect on the function of Sertoli cells which contributes to impairment of spermatogenesis after SCI (Ottenweller et al., 2000). Thus it appears that endocrine changes in the acute phase of SCI in rats may impair some aspects of Sertoli cell function and render these cells incapable of providing sufcient support for normal spermatogenesis (Huang et al., 1995). However, the severity of spermatogenic lesions makes it unlikely that hormone alterations represent the sole mechanism responsible for the spermatogenic damage in SCI rats (Saez, 1994; Huang et al., 1995, 1999b; Ottenweller et al., 2000). The Sertoli cells in the SCI rats appear to be unable to support normal spermatogenic differentiation additionally due to the lack of normal neural impulses (Huang et al., 1998). The absence of normal neural impulses may additionally perturb the
activities of Leydig cells (Huang et al., 1998). Lee et al. (2002) have indicated the existence of a neural pathway that originates in the brain and travels through the spinal cord, and they have suggested that this neural pathway plays a crucial role in Leydig cell function. This conclusion agrees with the nding that T9 -SCI causes regression of spermatogenesis in rats despite the relatively normal LH levels after the 14th day post-injury (Huang et al., 1995, 1998). Patterns of spermatogenesis in men with SCI The consequences of SCI on spermatogenesis have been demonstrated by several authors in testicular biopsy samples in the human. Standard pathological interpretations of the haematoxylin and eosin sections have classied biopsies from SCI men as Sertoli-cell-only syndrome, early maturation arrest (arrest at the stage of primary spermatocyte), late maturation arrest (arrest at the level of spermatid), hypospermatogenesis, or normal spermatogenesis. The term hypospermatogenesis indicates that all stages of spermatogenesis, including mature spermatozoa, are present in the seminiferous tubuli but the relative numbers of spermatozoa are decreased. Stemmermann et al. (1950) reported normal spermatogenetic pattern in six out of 16 SCI patients, hypospermatogenesis in three men, various phases of maturation arrest without spermatozoa in 6 men, and Sertoli-cell-only syndrome in one man. Bors et al. (1950) have found normal spermatogenesis in three men out of 34 paraplegic men, hypospermatogenesis in 17 men, and varying degrees of maturation arrest or Sertoli-cell-only syndrome in the remaining 14 men. Leriche et al. (1977) reported that 27 out of 54 testicular biopsies in SCI men showed seminiferous tubular atrophy and maturation arrest. The remaining 50% of the men demonstrated atypical ndings of normal spermatogenesis. Obstruction of the seminiferous tubules and hyperplasia of the Sertoli cells were occasionally presented in SCI men (Leriche et al., 1977). Perkash et al. (1985) observed normal spermatogenesis in six out of 13 SCI patients (46%). The remaining men demonstrated hypospermatogenesis (Perkash et al., 1985). A more recent study by Elliott et al. (2000) yielded consistent results. Spermatogenesis was normal in 28 out of 50 men with SCI. Hypospermatogenesis was demonstrated in 15 men (30%), late maturation arrest (arrest at the spermatid stage) was found in 6 men (12%), and early maturation arrest (arrest at the spermatocyte stage) was found in one man (2%). The latter two reports, in contrast to the earlier studies, tend to suggest that testicular biopsies in SCI men rarely demonstrate maturation arrest at the primary spermatocyte stage and that the Sertoli-cell-only syndrome pattern is not present (Perkash et al., 1985; Elliott et al., 2000).
145
Spinal cord injury
A hypothesis supporting a role of testicular hyperthermia in the development of testicular damage in SCI men (Wang et al., 1993) cannot be accepted unequivocally. Whether a probable elevation of scrotal temperature due to abnormal thermal regulation, attributable to the scrotal or testicular denervation, is the mechanism leading to defects in spermatogenic activity in SCI men needs research efforts to be elucidated. Brackett et al. (1994b) have provided evidence that scrotal and oral temperatures are not related to semen quality in SCI men. The correlation between the SCI level and the testicular biopsy ndings (Stemmermann et al., 1950; Leriche et al., 1977; Perkash et al., 1985; Elliott et al., 2000) appears to be controversial. Although Bors et al. (1950) demonstrated that men with cauda equina injury have more advanced spermatogenic proles compared with those with upper cord lesions, other investigators have not supported the above statement (Elliott et al., 2000). When multiple logistic regression analysis was employed by Elliott et al. (2000), using patient age, postinjury period, and serum hormonal proles to predict the outcome of testicular biopsy in men with SCI, no statistically signicant predictive factors for the type of testicular histopathology were revealed. Objective parameters of spermatogenesis evaluated by careful observation of testicular biopsy samples in men with SCIs show a decrease in seminiferous tubular mean number of late spermatids and a decrease in late spermatid/Sertoli cell ratio compared with fertile volunteer controls (Hirsch et al., 1991b). The employment of electron microscope in the observation of testicular biopsy specimens of men with SCI revealed several malformations of spermatids (mainly in the acrosome and the head and rarely in the tail) (Holstein et al., 1985). In some animal studies early spermiogenetic cellular changes have been noticed (i.e. vacuolisation of the nuclei of spermatids, abnormal nuclei of pachytene spermatocytes, and pyknosis of either spermatocytes or spermatids or spermatids) (Linsenmeyer et al., 1994; Hirsch et al., 1999; Huang et al., 2003). Molecular biology of the testis in men with SCI In a recent study, Brackett et al. (2008) have determined the sperm DNA damage in SCI men using the sperm chromatin structure assay and have reported that men with SCI present signicantly higher mean DNA fragmentation index in spermatozoa compared with control subjects. This nding may not be attributable to the prolonged anejaculation period or to the co-existing conditions of necrospermia or leucocytospermia (Brackett et al., 2008). In fact, the authors could not speculate a possible pathogenetic mechanism for the development of the sperm DNA damage (Brackett et al., 2008). In
146
another study, Talebi et al. (2007) investigated the nuclear DNA integrity of spermatozoa aspirated from the cauda epididymis of rats with SCI. They reported compromised sperm chromatin structure in SCI animals which might have a detrimental inuence on the fertilising potential of the spermatozoa. In a previous study, Hirsch et al. (1999), using a rodent model, attempted to determine quantitative alterations in the spermatogenesis and to evaluate the sperm chromatin structure at both the acute and chronic phases following the SCI. Assessment of spermatogenesis using quantitative histometry and DNA ow cytometry analysis revealed defects in the spermatogenic process occurring soon after the SCI (in the acute phase) and persisting through the chronic phase in approximately 25% of the subjects. In addition, in this study (Hirsch et al., 1999), a lack of correlation has been demonstrated between spermatogenic function and neurologic status (the neurologic status was objectively assessed using the modied Tarlov scale) (Hirsch et al., 1999). Hou et al. (1995), have shown that sperm nuclear maturity (assessed by acidic aniline blue stain) is not affected by SCI. On the other hand, Engh et al. (1993) using ow cytometry to assess sperm quality have found high degree of abnormal chromatin condensation and reduced binding of a uorescent acrosomal marker. The disparate responses of two Sertoli cell proteins to SCI in rats (i.e. transferrin- mRNA transcript is reduced in SCI rats, whereas, androgen binding protein-mRNA transcript has remained unaffected in SCI rats) (Huang et al., 1995) may conrm that hormonal alterations do not represent the only mechanism responsible for the impairment in spermatogenesis immediately after the occurrence of SCI (Huang et al., 1995). The levels of mRNA transcripts for the spermatogenic cell-specic hemiferrin and spermatid-specic transition protein 2 and protamine 1 involved in the condensation and maturation of the male gamete nucleus did not demonstrate any simultaneous alterations in rats with SCI (Huang et al., 1995). This may suggest that the degeneration of spermatids in subjects with SCI is not caused by an intrinsic spermatid cellular/molecular defect. Another study in rats with spinal contusion revealed decreases in the mRNA transcripts for spermatid-specic protamine 1 and transition protein 2 (Huang et al., 2003). The latter decreases did not correlate with the serum levels of either testosterone or FSH (Huang et al., 1999b, 2003; Ottenweller et al., 2000). The results of the study by Huang et al. (2003) demonstrate specic effects of spinal cord contusion on spermiogenesis. In that study, Huang et al. (2003) monitored the levels of mRNA for cyclic adenosine monophosphate (cAMP) responsive element modulator (CREM). A precocious expression of CREM in early spermatocytes and a lack of it in young
Spinal cord injury
spermatids during the acute phase after spinal cord contusion has been observed. This may indicate abnormal cAMP signalling in the acute phase. CREM is a nuclear transcription factor that upon phosphorylation modulates the function of cAMP-responsive genes. Thus CREM serves as a functional switch for post-meiotic germ cell differentiation (Sassone-Corsi, 1998). Furthermore, it is known that cAMP signalling mediates the effects of FSH on Sertoli cells (Means et al., 1976) and it might mediate some of the effects of androgens (Heinline & Chang, 2002). These changes in the adenylate cyclase/cAMP pathway in subjects with spinal cord contusion could disrupt the differentiation of spermatogenic cells and could result in the formation of spermatozoa with abnormal morphology or function. It should be mentioned that SCI alters the consequences of exogenous testosterone (T) administration on sperm production (Huang et al., 2004). These alterations in testicular exocrine function may be associated with an altered cAMP/CREM signalling in spermatogenic cells of SCI rats. Huang et al. (1999a) have demonstrated the persistence of spermatogenesis in Sertoli cell enriched (SCE) testes during the chronic phase of SCI. These effects are associated with elevated levels mRNA for Sertoli cell FSH receptor and androgen receptor. It has been postulated that absence of spermatogenic cells in most of the seminiferous tubuli, and/or Sertoli cell enrichment in the SCE testis may render the spermatogenic stem cells and/or undifferentiated spermatogonia cells less susceptible to the deleterious effects of SCI on the normal testes. The latter cells in the SCE testis are able to proliferate and differentiate after SCI. In the SCESCI rat model, the changes in Sertoli cell physiology may render the intratesticular paracrine environment more favourable for the survival and proliferation of the remaining stem cells, thus resulting in the persistence of spermatogenesis during the chronic phase of SCI (Huang et al., 1999a). The alterations in FSH-Sertoli cell interactions, in the SCESCI model may additionally disrupt paracrine feedback mechanisms between Sertoli and Leydig cells resulting in an increased production of intratesticular testosterone, and perhaps of other paracrine factors, such as beta-endorphin, which could further stimulate Sertoli cells altering their normal function (Morris et al., 1987; Fabbri et al., 1988; Huang et al., 1999a). Testicular beta-endorphin is mainly produced by Leydig cells and modulates the Leydig cell testosterone production (Chandrashekar & Bartke, 1992). Sperm parameters after SCI In previous studies some investigators have suggested that the semen analysis in spinal cord injured men, in the
chronic phase, demonstrates low (Perkash et al., 1985) to normal (Momen et al., 2007) sperm count and low sperm motility (Perkash et al., 1985; Brindley et al., 1986; Brackett et al., 1995). In the international literature there is limited data on human semen characteristics in the acute phase after SCI. Mallidis et al. (1994) Sertoli cell enrich demonstrated normal semen parameters, after the initial SCI shock, until the 16th day post-injury. After that period, a constant decrease in sperm motility and viability was observed. A canine model of SCI indicates a signicant decline in spermatogenesis at 3 weeks following SCI compared with non-SCI dogs (Ohl et al., 2001). A study of spinal cord injured rats shows a similar impairment in spermatogenesis during the acute phase after SCI (Linsenmeyer et al., 1994). During the chronic phase, however, Brackett et al. (1998b) have shown that there is no further progressive deterioration of the sperm parameters in SCI men. Many theories have been proposed in the past to explain the impairment of sperm motility in SCI men. Urinary tract infections (UTI), testicular hyperthermia, changes in sex hormonal proles, antisperm antibodies, sperm stagnation in the male reproductive ducts (due to anejaculation) (Brindley, 1982; Beretta et al., 1989; Linsenmeyer & Perkash, 1991; Momen et al., 2007), diminished blood ow to the gonads due to lower cardiac output, or stress related factors have been proposed to contribute to the aetiology of the lower sperm motility proles in SCI subjects compared with controls (Brackett et al., 1996b; Sonksen & Ohl, 2002a,b). The study of the SCI rat model demonstrates that the impaired sperm motility resulting from minor SCI is reversible, whereas defects in sperm motility in severe SCI or spinal cord contusion might be permanent (Huang et al., 1995, 1999b, 2003). In addition, it has been shown that repeated minor contusions may impair sperm motility as much as does a single contusion with greater force (Huang et al., 2003). Impaired sperm motility in SCI subjects (Billups et al., 1990) may be additionally due to a defect in epididymal sperm maturation process (Sedor & Hirsch, 1995). Brackett et al. (1997) have shown that sperm motility, particularly rapid linear motility, decreases faster in specimens recovered from SCI men compared with the controls. This effect is exacerbated at body temperatures (37 C). The inuence of the neurological level of the SCI on the presence of spermatozoa or the sperm motility in the ejaculate is a nonwell established issue. Some investigators have reported higher success rate (i.e. presence of spermatozoa) in tetraplegic subjects than in paraplegic subjects (Le Chapelain et al., 1998). Patients who manage their lower urinary tract problems with intermittent catheterisation may have better
147
Spinal cord injury
sperm qualitative and quantitative parameters than those employing indwelling catheters (Szasz & Carpenter, 1989). Sperm morphology is detrimentally affected by SCI. A study employing electroejaculation procedures in men with SCI reveals signicantly higher percentages of spermatozoa with abnormally small sperm heads, vacuolated sperm heads and tail defects in comparison with control subjects (Sedor & Hirsch, 1995). As we have previously mentioned, sperm viability is also affected in SCI men. Necrospermia (presence of dead spermatozoa) is a well-known phenomenon associated with SCI. The percentages of dead spermatozoa are significantly higher in SCI men than in normal men regardless of the level of injury (Brackett et al., 1998a). Brackett et al. (1998a) have suggested that the method used to collect spermatozoa from SCI men and the method employed to achieve ejaculation play a role in the quality of the retrieved sperm sample. The percentage of dead spermatozoa is signicantly lower in antegrade versus retrograde specimens and in specimens produced by vibratory stimulation versus electroejaculation (Brackett et al., 1998a). The per cent of dead spermatozoa is also higher in SCI men at any time post-ejaculation compared with controls. On the other hand, Brackett et al. (1997) have provided evidence that the rate of sperm cellular death as a result to exposure to heat in SCI men is not signicantly faster compared with control men. The inuence of SCI on sperm motility parameters and the other quantitative and qualitative sperm parameters should be taken into consideration when spermatozoa are recovered from spinal cord injured men and processed for assisted reproductive technology. Seminal plasma biochemistry and SCI Secretions of male accessory genital glands. Brackett et al. (2000) have shown that in SCI men motility and viability of spermatozoa aspirated from the vas deferens are significantly higher before the contact of spermatozoa with the seminal plasma. In addition, sperm samples aspirated from vas deferens of SCI men have lower motility and viability compared with a control group. In the latter study the control group included a group of men who underwent routine elective vasectomy. This observation may suggest that epididymal or testicular factors play a role in the lower motility proles of spermatozoa from men with SCI (Brackett et al., 2000). However, some seminal plasma factors may additionally account for the impairment in sperm motility in spinal cord injured men. A comparison of biochemical constituents of semen recovered from SCI men (using electroejaculation procedure) and from normal individuals reveals a lower concentration of albumin, fructose, alkaline phosphatase and
148
glutamic oxaloacetic transaminase in SCI men (Hirsch et al., 1991a). In contrast, a higher concentration of chloride in the semen of SCI men has been demonstrated. These biochemical abnormalities may result from alterations in the function of the accessory genital glands due to the neurological injury or from the electroejaculation procedure itself and may contribute to the decreased sperm motility in SCI men (Hirsch et al., 1991a). Leucocytes and cytokines in the semen. An elevated leucocyte count in the semen of SCI men is quite common even in the absence of concomitant UTI. On the other hand, recurrent infections of the genitourinary tract and a subsequent leucocytospermia are present in 6070% of men with SCI. In normal men, leucocytospermia reduces sperm motion parameters and decreases sperm viability (Wolff et al., 1990; Trabulsi et al., 2002). The latter defect in sperm fertilising capacity may be attributed to the adverse effects of reactive oxygen species (ROS) on sperm function (Trabulsi et al., 2002). In SCI men with concomitant UTI, an elevated seminal neutrophil and macrophage concentration is found (Aird et al., 1999; Trabulsi et al., 2002) (Fig. 2). In Bracketts laboratory, Randall et al. (2003) have provided evidence that leucocytospermia in SCI men is not related to histological inammatory changes in the prostate. In the same laboratory, cytouorographic identication of activated T-cell subpopulations in the semen of SCI men has shown that the largest proportion of the leucocytes is represented by T-cells expressing human leucocyte antigen HLA-DR and CD25 (Basu et al., 2002). These cells, being in an activated state, secrete cytokines in the seminal plasma. Basu et al. (2004) demonstrated elevated concentrations of the cytokines IL1b, IL6, IL12, IFNc and TNFalpha, and lower concentrations of IL4 and TGFbeta1 in the seminal plasma of men with SCI compared with non-SCI healthy control subjects. Some of the cytokines that had been elevated in SCI men were either not detectable or not present in the seminal plasma of control subjects. This observation tends to suggest a cell mediated versus a humoral immunologic basis for infertility in the SCI men. Simultaneous measurements of blood cytokines in SCI men revealed no signicant elevation (Basu et al., 2002, 2004). Thus it has been suggested that the observed inammatory response in SCI men is restricted to the urogenital tract (Basu et al., 2004). The employment of the combination of specic monoclonal antibodies against human cytokine interleukin 1 beta (IL1-b), interleukin 6 (IL6), and tumour necrosis factor alpha (TNF-a) to neutralise cytokine activity in the seminal plasma results in a signicant elevation in sperm motility (Cohen et al., 2004). In another study originated from Bracketts laboratory, the investigators have shown that the neutralisation
Spinal cord injury
Fig. 2 Relationship between cytokines and male fertility in spinal cord injured men. IL1-b, interleukin 1-b; IL6, interleukin 6; TNFa, tumour necrosis factor a; INFc, interferon c; ROS, reactive oxygen species; NFjB, nuclear factor jB; Relevant references (Wang et al., 1981; Pandya & Cohen, 1985; Hill et al., 1987; Aitken et al., 1989; Takao et al., 1990; Miesel & Weser, 1991; Buch et al., 1994; Rajasekaran et al., 1995; Vicino et al., 1999; Camejo et al., 2001; Robertson et al., 2002; Basu et al., 2004).
of the activity of some of the above cytokines (IL1-b, IL6 and TNFa) at the receptor level in the semen plasma of SCI men has benecial consequences on sperm motility in these patients (Brackett et al., 2007a). Reactive oxygen species. Semen samples from SCI men demonstrate higher levels of ROS than samples from infertile men regardless of the method of ejaculation (either electroejaculation or vibratory stimulation) or the type of specimen (either anterograde or retrograde) (de Lamirande et al., 1995). The precise role of ROS such as superoxide (dO2) anion, hydrogen peroxide, peroxyl and hydroxyl in male infertility has not been well established yet. Under normal conditions ROS are important for the regulation of the sperm capacitation process and the sperm acrosomal reaction process (Sharma & Agarwal, 1996). Leucocytes, morphologically normal but functionally abnormal spermatozoa and morphologically abnormal spermatozoa can produce abnormally high levels of ROS (Sharma & Agarwal, 1996). Elevated levels of ROS in leucocytospermic semen samples of men with SCI are associated with increased concentrations of cytokines and decreased superoxide dismutase activity in the semen (de Lamirande & Gagnon, 1992; Agarwal et al., 1994; Padron et al., 1997). High levels of ROS in the microenvironment of the spermatozoon or in the spermatozoal cytoplasm
may lead to an increase in the lipid peroxidation of the spermatozoal membrane and a reduction in the sperm membrane uidity in semen samples of men with SCI. Wang et al. (2007) have demonstrated that in spinal cord injured rats antioxidant treatment with vitamin E has a protective effect on sperm parameters. ROS may cause decreases in sperm forward motility by reducing the sperm intracellular ATP concentration (Harrison et al., 1991; de Lamirande & Gagnon, 1992). Seminal vesicular secretions and leucocyte activation. Nevertheless, leucocytospermia is not the only responsible factor for the impaired semen quality in SCI men. Ablebodied fertile men with leucocytospermia show normal sperm motility and sperm number. Thus the presence of protective components in the seminal uids of the above population that overcome the effects of leucocytospermia may be suggested (el-Demiry & James, 1988; Harrison et al., 1991). The fact that immunohistological analysis of the seminal vesicles in humans shows only small numbers of leucocytes in its epithelium and interstitium may suggest that immunosuppressive substances secreted by the seminal vesicles contribute to the inhibition of leucocyte activation and accumulation (Hellstrom et al., 1989; Jeulin et al., 1989; Aumuller & Riva, 1992; Gonzales et al., 1992). Measurements of fructose, which is considered to
149
Spinal cord injury
be a marker of seminal vesicular secretory function, show a signicant decrease in the ejaculates of SCI men (Hellstrom et al., 1989; Jeulin et al., 1989; Hirsch et al., 1991a; Aumuller & Riva, 1992; Gonzales et al., 1992). This may indicate the presence of seminal vesicular secretory dysfunction in SCI men. Subsequently the secretion of superoxide dismutase and catalase by the seminal vesicles is reduced. Thus the total antioxidant capacity of the seminal plasma of SCI men may be diminished, allowing ROS to exert their detrimental effects on sperm membrane function. The combination of leucocytospermia and alterations in the seminal vesicular function may suggest that synergistic factors account for the low sperm motility in SCI men (Gonzales et al., 1992; Trabulsi et al., 2002). Dashtdar & Valojerdi (2008) focused their scientic efforts to evaluate a probable effect of SCI on the seminal vesicular epithelium in adult male rats with surgical transection at the level of T9. Employing light microscopy the authors were able to observe 5 days after the operation acute inammation of the seminal vesicles including vasodilatation and migration of leucocytes to the epithelium. Moreover, transmission electron microscopy revealed signicant changes in the seminal vesicular epithelium such as (a) decrease in dimensions of rough endoplasmic reticulum, secretory granules and Golgi apparatus, (b) accumulations of fat droplets and lipofuscin in the cytoplasm, (c) euchromatinised and swollen nuclei, (d) decrease in cellular diameters and (e) the presence of macrophages and hollow spaces in the epithelium (Dashtdar & Valojerdi, 2008). The above ndings suggest the presence of seminal vesicular dysfunction in the acute phase of SCI. Unfortunately the experimental protocol in the above study (Dashtdar & Valojerdi, 2008) included no observations for the chronic phase of the SCI. Platelet activating factor acetyl hydrolase. Another constituent of the seminal plasma that shows abnormal levels in electroejaculates of SCI men (Hirsch et al., 1991a) is the platelet activating factor acetyl hydrolase (PAFah) which originates mainly from the prostate and the seminal vesicles. The latter substance has been found to have a significantly higher activity in the seminal plasma of SCI men than in healthy men. The enzymatic activity of PAFah is negatively correlated with sperm motility (Ricker et al., 1989; Zhu et al., 2006). This is because PAFah catalyses hydrolysis of esteried PAF at the sn-2 position producing acetate and biologically inactive lyso-PAF. On the other hand, PAF is an autocrine modulator of sperm motility that stimulates sperm motility and enhances sperm capacitation and the acrosome reaction process (Sengoku et al., 1993; Fukuda et al., 1994; Hou et al., 1995; Odeh et al., 2003). This high activity of PAFah in
150
the seminal plasma of SCI men (compared with the healthy men) may contribute to the development of low sperm motility in SCI men. Sexual abstinence and semen quality in SCI men. The inuence of the seminal plasma of SCI men on sperm motility has been evaluated extensively. Seminal plasma from normal men has been found to improve motility of spermatozoa of SCI men (Brackett et al., 1996a). Spermatozoa from the vas deferens from SCI men have good motility (Brackett et al., 2000). However, spermatozoa present in the ejaculates of SCI men have poor quality (Denil et al., 1992). This phenomenon (i.e. low sperm quality in the ejaculates of SCI men) is independent of the period of sexual abstinence, implicating disordered storage of spermatozoa within the seminal vesicles due to the SCI pathophysiology rather than due to infrequent ejaculation (Ohl et al., 1999). Prolonged anejaculation may induce the development of anti-sperm antibodies but the available evidence regarding their role in the development of male infertility after SCI is conicting. On the other hand, repeated ejaculations do not change the spermatozoal quality of SCI men (Sonksen et al., 1999; Das et al., 2006). This fact may suggest that stagnation in the seminal ducts due to infrequent ejaculations is not the cause of the poor spermatozoal parameters in SCI men (Sonksen et al., 1999). The interesting observation of brown-coloured semen (rusty pipe syndrome) in at least one ejaculation of almost one fourth of SCI men is of unknown aetiology and may be related to the seminal vesicular dysfunction (Wieder et al., 1999). Testosterone-repressed prostate message 2 m-RNA and PSA. Using a rat model of SCI, Huang et al. (1997) have shown that there is an acute but temporal impairment in the autoregulation of androgen receptor mRNA by its own ligand shortly after the induction of SCI and a persistent elevation of testosterone-repressed prostate message 2 m-RNA (TRPM-2). The TRPM-2 gene product and its related proteins are involved in the regulation of apoptosis process. In this regard, expression of TRPM-2 is induced or greatly enhanced in a number of tissues undergoing apoptosis (Russo et al., 1994). The elevation of TRPM-2 mRNA is associated with a decrease in prostatic epithelial cell height and the prostate weight in SCI rats (Huang et al., 1997). This effect may be attributed to the absence of normal innervation to the prostate and the lack of normal androgen regulation of prostatic function after SCI. It should be mentioned that serum testosterone in SCI rats returns to normal levels within the rst month post-SCI and therefore cannot be exclusively responsible for the above prostatic effects (Huang et al., 1997).
Spinal cord injury
Recently in another study, Hvarness et al. (2007) compared prostatic volume in men with SCI and men without SCI employing transrectal ultrasonography. In the latter study the authors concluded that men with SCI have a smaller prostate than those without SCI. An unanswered question is whether the neurological damage in SCI men contributes to the prostatic secretory dysfunction (Hvarness et al., 2007). To evaluate whether there is an alteration in prostate secretory function in SCI men, Lynne et al. (1999) had assessed the PSA as a marker of prostatic secretory activity. PSA is a 30 kDa serine protease that cleaves biological substrates in seminal uid, including seminogelin I, seminogelin II and bronectin, into small peptides; the action of PSA may result in increased sperm motility (Lilja & Lundwall, 1992; Kise et al., 1996). PSA has also been shown to cleave other substances, including insulin-like growth factor-binding protein-3 and laminin. This may indicate a potential role of PSA in the regulation of various biological functions (Peehl, 1996; Plymate et al., 1996). PSA reaches the blood from the prostatic acini where it is secreted by diffusion through the epithelial cell membrane into the stroma and the nearby capillaries under normal conditions. In pathological conditions such as (a) disturbances in innervation or (b) presence of local processes such as prostatitis which disrupt the cytoarchitecture, leakage into the capillaries is facilitated. As it has been shown by Lynne et al. (1999), men with SCI have elevated serum and decreased seminal total PSA concentrations compared with normal subjects even when no other factor such as prostatitis could account for it. In other studies it has been demonstrated that SCI patients have decreased total seminal PSA but normal concentrations of total serum PSA (Alexandrino et al., 2004). The decrease in prostatic contributions to the semen in SCI men may result in lower concentrations of citrate, zinc and cholesterol in the seminal plasma, molecules known to be important for the development and maintenance of optimal sperm motility (Sofikitis & Miyagawa, 1993). Therapeutical approach for the spinal cord injured patient Nowadays it has become clear that the sexuality in men with SCI depends on the damage to the different spinal cord regions that are responsible for regulating the normal sexual function. As a result, in general, in SCI men we may expect loss of psychogenic erections, reexogenic erections, ejaculation, sensation of orgasm, or fertility; or loss of several of the above functions. Most SCI men are usually younger than 45 years and several studies have reported a frequency of erection in 5495% of them, whereas performance of successful coitus ranges from 5% to 75% of
them, and ejaculation ranges from 3% to 20% of them (Bors & Comarr, 1960; Grifth et al., 1973; Biering-Sorensen & Sonksen, 1992; Eid, 1992). Even more controversial is the incidence of impregnations in couples attempting conception without medical assistance. Natural pregnancy has been reported to occur in 0% to 5% of SCI men (Grifth et al., 1973; Rawicki & Hill, 1991; Boone et al., 1997). This extremely low incidence of fertility reects the erectile and ejaculatory disturbances that men with SCI present. However, erectile dysfunction and anejaculation do not represent the only causes of infertility. Several studies have demonstrated poor quantitative and qualitative parameters of spermatozoa obtained from men with SCI by methods of assisted ejaculation (Halstead et al., 1987; Brackett et al., 1994a,b, 1996a). Nowadays, the therapeutical andrological approach of SCI men focuses on achievement of erectile function, recovery of spermatozoa and assisted reproductive technology. Sexual function Treatment of sexual dysfunction in spinal cord injured males is frequently centred in the erectile deciency. Modern approaches emphasise the need for sexual health counselling where broader issues of intimacy, relationship and communication with the female partner are addressed. Sexual activity in men with SCI may have additional positive consequences such as relief from spasms following ejaculation (Courtois et al., 2004). Physical management is important. For instance, Kuhn (1950) reported that slight movements of the prepuce over a sharply circumscribed reexogenous area (including the movement of corona of the glans and the penile fraenulum) were the most effective stimulus for the elicitation of penile erection. Likewise, Comarr (1970) showed that erection may be enhanced and maintained with catheter manipulation, usage of lower limb spasticity, precoital bladder emptying and application of hot towels to the penile shaft. Other authors have reported improved erections with the usage of penile vibratory stimulation (PVS) and venous constrictive band at the root of the penis (Francois et al., 1983). Vacuum erection devices such as electric or manual vacuum pumps have been used for many years. Several authors reported a successful rate for achieving erection (using such devices) in SCI men ranging from 72% to 93%. The overall patient satisfaction rate with the device was also high (Lloyd et al., 1989; Zasler & Katz, 1989; Denil et al., 1996). The pharmacological management and more specically the employment of phosphodiesterase type 5 inhibitors is also effective in SCI patients (Derry et al., 1998; Giuliano et al., 1999; Maytom et al., 1999). Sildenal citrate was
151
Spinal cord injury
used initially only in SCI individuals with intact reexogenic erectile responses (Derry et al., 1998; Giuliano et al., 1999; Maytom et al., 1999). However, in another study it has been suggested that sildenal citrate is effective in SCI men with no residual erectile function (Monga et al., 1999). Subsequently, it has been suggested that the usage of sildenal is effective in the improvement of the erection when at least one component of the erection phenomenon either psychogenic or reexogenic is preserved (Monga et al., 1999; Schmid et al., 2000). On the other hand, absence of both psychogenic and reexogenic erections appears to exclude a successful response to sildenal (Schmid et al., 2000). Alternatively, for a subpopulation of SCI men, it has been found that the longer therapeutical window of tadalal may make it more suitable than sildenal (Del Popolo et al., 2004; Giuliano et al., 2007). Vardenal was most recently studied in a double-blind, placebo-controlled parallel-group-12-week investigation of 418 men with SCI (Giuliano et al., 2006). In the latter report, all the assessed parameters including ability to maintain an erection, capacity to achieve penetration and ability to ejaculate were signicantly improved under treatment with vardenal compared with placebo administration. Adverse events associated with the usage of PDE5 inhibitors in SCI men included headache, dyspepsia, dizziness, abnormal vision, rhinitis/respiratory tract infections/disorders, diarrhoea, rash and ushing. These adverse effects were transient and mild to moderate (Giuliano et al., 1999; Maytom et al., 1999; Schmid et al., 2000). Absolute contraindication to the prescription of these PDE5 inhibitors represents the usage of nitratecontaining medications (Monga et al., 1999). This is an important contraindication as some SCI individuals may use nitrate-containing medications to treat AD. Another therapeutic method to produce erection in SCI men is the intracavernosal injection of vasoactive drugs (Virag, 1982; Beretta et al., 1986; Sidi et al., 1986, 1987; Bodner et al., 1987; Sonksen et al., 1990; Earle et al., 1992; Kapoor et al., 1993; Chao & Clowers, 1994; Hirsch et al., 1994; Zaslau et al., 1999). A success rate up to 95% is not uncommon in SCI men when success is dened as the achievement of erection adequate for penetration (Bodner et al., 1987; Kapoor et al., 1993). It should be taken into consideration that the denervated tissues are very sensitive to the drugs used for intracavernosal injection (Beretta et al., 1986; Sidi et al., 1986, 1987; Bodner et al., 1987; Earle et al., 1992; Kapoor et al., 1993). Main complications with injection therapy in SCI men include the risk of prolonged erection (priapism) and brosis in the corporal tissue (Juenemann & Alken, 1989). Alternatively to the usage of intracavernosal injections, Sonksen & Biering-Sorensen (1992) obtained positive therapeutic results in impotent SCI men using nitroglyc152
erine plasters placed on the skin of the penile shaft. The complications of this method are primarily related to allergic dermatitis and headache. The headache requires only mild analgesics. Similarly, topical application of papaverine and prostaglandin E1 gel to the penis, scrotum and perineum has resulted occasionally in erection (Kim & McVary, 1995; Kim et al., 1995). Intraurethral prostaglandin E1 (alprostadil) has also been used for the treatment of erectile dysfunction in men with SCI. However, its efcacy has not been sufcient (Bodner et al., 1999). While the therapeutic trend for SCI men is towards the administration of phosphodiesterase 5 inhibitors, options such as sacral anterior root electrical stimulation and even penile prostheses continue to have a place in the clinical care. Brindley (1994) and Brindley & Rushton (1990) have demonstrated that the sacral anterior root stimulator for bladder control can also be used to obtain erection. The most appropriate root for stimulation is usually the S2. However, stimulation of the S3 root might be more effective in few men. The frequency for stimulation may be 9 Hz (Brindley, 1995). Finally, the surgical insertion of penile prostheses (rigid, semi-rigid and inatable) has also been attempted in SCI men for several years to obtain a successful erection for intercourse (Golji, 1979; van Arsdalen et al., 1981; Dietzen & Lloyd, 1992). However, complications such as infection, tissue breakdown and extrusion of the prosthesis occur more frequently in men with SCI than in other populations in whom penile prostheses have been placed (van Arsdalen et al., 1981; Rossier & Fam, 1984; Kabalin & Kessler, 1988; Dietzen & Lloyd, 1992). The loss of sensation and vasomotor control and the frequent UTI represent the main causes for a higher operative risk in SCI men than in other patient populations. The implantation of penile prostheses to achieve erection may be recommended as the last therapeutic option in this group of patients.
Sperm recovery Nonsurgical sperm recovery for assisted reproduction technology in SCI men Pharmaceutical agents. Guttmann & Walsh (1971) reported that the intrathecal injection of a cholinesterase inhibitor (prostigmine) resulted in several spontaneous ejaculations over several hours with a successful rate up to 58%. The authors observed that there was less likelihood of ejaculation if the lesion was between T10 and L4. Other investigators employed either subcutaneous injection of physostigmine (Chapelle et al., 1988) or intrathecal injection of neostigmine (Piera, 1973) (Table 1). However, the latter treatments were abandoned by most
Spinal cord injury
physicians because of a high incidence of severe side effects such as AD. Death from a cerebral haemorrhage has been reported after the intrathecal injection of prostigmine in one man with C-6 quadriplegia (Guttmann & Walsh, 1971). In another report, the authors proceeded with subcutaneous administration of the short-acting drug physostigmine after pre-treatment with N-butylhyoscine to reduce any side effects (Jesionowska & Hemmings, 1991). The above therapeutical approach has been combined with masturbation or a vibrator (Chapelle, 1983; Chapelle et al., 1983; Jesionowska & Hemmings, 1991) with successful results. However, today subcutaneous administration of cholinesterase inhibitors is not recommended as a rst choice of treatment (Ohl & Sonksen, 1996). In an effort to nd a replacement therapy to facilitate self-ejaculation in men with SCI, investigators have considered the administration of oral midodrine when PVS is attempted as treatment for retrograde ejaculation or for semen transport disturbances (Staerman et al., 2001; Blanchard-Dauphin et al., 2005). Midodrine is an a1adrenergic agonist currently used for treating hypotension (a common condition among patients with SCI) and modies arterial resistance and venous capacitance. It is absorbed fairly rapidly with a peak concentration within 2040 min and a short half-life of approximately 30 min.
The rationale to use midodrine is the fact that this medicine targets the sympathetic system (as opposed to the entire autonomic system) (Soler, 2005). Thus it may have fewer side-effects than the previously used cholinesterase inhibitors. In fact, several studies have shown promising results of midodrine in the treatment of both retrograde ejaculation and anejaculation in patients with SCI (Schwale et al., 1980; Riley & Riley, 1982; Staerman et al., 2001). However, although the side effects of midodrine are mild including mainly goose skin, tingling of the skin and pruritis, especially of the scalp, its usage has also been associated with high systolic blood pressure and mean arterial pressure (Soler et al., 2007). Moreover, other investigators reported cases of AD in SCI men treated with midodrine (Staerman et al., 2001). The above cardiovascular modications depend on the level of the lesion with more profound AD developed in patients with quadriplegia than in the remaining men with SCI (Sheel et al., 2005). The usage of midodrine results in a high rate of achieving ejaculation especially in patients with complete SCI lesions above T10. It should be emphasised that monitoring the blood pressure (during midodrine usage) to assess a possible development of AD (McBride et al., 2003; Elliott, 2006; Elliott & Krassioukov, 2006) is mandatory particularly in men with quadriplegia.
Table 1 Sperm retrieval success rates in studies involving pharmaceutical treatment, prostate massage, electroejaculation, penile vibratory stimulation or surgical sperm retrieval techniques in selected populations of patients with spinal cord injury Method of sperm retrieval Cholinesterase inhibitors Prostigmine Physostigmine Neostigmine Level of SCI T10 or above Success rates (%) 58 55.5 27 31.9 5090 Relevant references (Guttmann & Walsh, 1971) (Chapelle et al., 1988) (Piera, 1973) (Arafa et al., 2007) (Brackett et al., 1998c) (Sonksen et al., 1994) (Nehra et al., 1996) (Sobrero et al., 1965) (Brindley, 1981) (Brackett et al., 2007b) (Ohl et al., 1997) (Momose et al., 1995) (Nehra et al., 1996) (Sonksen & Ohl, 2002) (Brinsden et al., 1997) (Warner et al., 1986) (Momose et al., 1995) (Brindley et al., 1986) (Lochner-Ernst et al., 1997) (Dahlberg et al., 1995) (Hirsh et al., 1993) (Chen et al., 1998) (Elliott et al., 2000)
Prostatic massage Penile vibratory stimulation
Electroejaculation
Level of SCI T11 or below Level of SCI T10 or above
15 77100
Surgical techniques
Level of SCI T11 or below Brindley reservoir Microsurgical aspiration of spermatozoa from vas deferens Testis biopsy
63 100 100
86
153
Spinal cord injury
Prostatic massage. A less problematic and faster technique for semen retrieval in SCI men is the prostatic massage. Its efcacy has been reported by several authors (Fahmy et al., 1999; Marina et al., 1999; Hovav et al., 2000; Okada et al., 2001; Arafa et al., 2007). The patient is placed in lateral decubitus position which is the most practical for manipulations in SCI men. The physician inserts the index nger into the patients anus. Then a sequential massage of the ampulla of vas, seminal vesicles and the prostate is applied for 60 s. The prostate massage should be vigorous by applying rm pressure against the pubic symphysis while the pad of the index nger should pass in a downward and medial direction in a rolling motion. The procedure may be repeated several times (Fahmy et al., 1999). Penile vibratory stimulation and electroejaculation. The most common, however, medically assisted procedures for the treatment of anejaculation in SCI men are PVS and electroejaculation. To apply PVS, a hand-held vibrator is placed against the dorsum of the glans penis or the frenulum of the penis and mechanical stimulation leads to activation of the afferent bres in the dorsal nerve of the penis and subsequent ejaculation (Sonksen & Ohl, 2002). To apply electroejaculation, a probe containing ventral electrodes and a thermistor to protect against thermal injury are placed into the rectum and electrical stimulation is rhythmically delivered to stimulate the pelvic nerve afferents through the wall of the rectum and subsequently to cause the release of semen (Halstead et al., 1987; Brackett, 1999b). (a) Penile vibratory stimulation: The rst employment of PVS to induce ejaculation was described by Sobrero et al. (1965). Many investigators have reported successful results in achieving ejaculations using this technology. This technique has been rened by Brindley (1981). The procedure of PVS involves orientation of the patient to the procedure and taking a complete medical history with attention to a history of developing AD. The level of SCI and prior attempts for ejaculation should be recorded if a patient is at risk for AD (i.e. injury level at T6 or higher or history of AD). The patient is seated in a multi-positional examination table or a hospital-type bed, and is administered 1040 mg of the calcium channel antagonist nifedipine, sublingually, 15 min prior to PVS. In patients with a very labile blood pressure additional administration of 0.4 mg of nitroglycerine sublingually, half a minute prior to PVS, is advisable. Monitoring blood pressure every minute in all patients during PVS is mandatory. If the patients ejaculation history suggests the presence of retrograde ejaculation or ejaculation of urine together with the semen, the bladder must be properly prepared, approximately
154
10 min before PVS. The bladder of such patients should be drained by urinary catheterisation and 2550 ml of a buffer appropriate for spermatozoa washing should be instilled into the bladder (Chen et al., 1995). Oral alkalisation of the urine 48 h before the PVS session is recommended. The next step to apply PVS is placement of the vibrator on the glans of the penis and application of PVS for a total of 15 min in intervals of 23 min stopping to inspect the penile skin. PVS procedure is paused if (a) the penile skin bleeds or becomes oedematous, (b) the patients blood pressure rises to a high level, (c) ejaculation occurs or (d) the patient requests so. One to three professionals (depending on patients spasticity during ejaculation, probable occurrence of AD and patients ability to use hands) are needed to hold the vibrator, collect semen and attend to patients symptoms. Somatic responses are observed in 100% of trials that result in ejaculation (either anterograde or retrograde). Somatic responses involve: contraction of the abdominal muscles, spasticity below the level of injury, knee exion, hip exion and abduction of the thighs. Periurethral muscle contractions may be felt in most of the trials in which ejaculation has occurred. When no anterograde ejaculate is obtained while somatic responses are present, one should check for retrograde ejaculation. Evaluation for retrograde ejaculation should also be performed if the volume of anterograde ejaculates is low (<0.5 ml) or if the sperm count is unexpectedly low (compared with the previous ejaculation trials). A bladder catheter is inserted and the bladder contents are emptied by gravity. Then a volume of 2530 ml of sperm washing medium is used to lavage the bladder. If the contents of the recovered uid are cloudy, a second lavage is recommended. Relative contraindications for PVS are severe inammation of the penile skin, a penile prosthesis, untreated hypertension or cardiac disease and high risk of AD. Patients inability to comprehend instructions about the procedure represents also a contraindication. In addition, patients recently injured (i.e. <18 months) may not respond readily to PVS. Apart from the above mentioned contraindications, any man with SCI is a candidate for PVS regardless of the level of injury (Brackett, 1999b). Successful employment of PVS may be predicted by the preservation of the hip exion reex or the bulbocavernosus reex (Szasz & Carpenter, 1989). Recently, Brackett et al. (2007b) in an effort to increase the efcacy of the PVS technique used two vibrators in men with SCI who failed to ejaculate with one vibrator. With the glans of the penis sandwiched between two vibrators, the nonresponders (to the previously mentioned classic technique) demonstrated better results. The loss of
Spinal cord injury
erection is not an indication to stop vibrostimulation. On the other hand the presence of a hard erection is not a reliable predictor of ejaculation (Szasz & Carpenter, 1989; Elliott, 2003). This dissociation between erection and ejaculation is also seen in other neurogenic conditions such as post-radical prostatectomy (i.e. absence of ejaculation) and multiple sclerosis. Almost all men (98%) with intact bulbocavernosus reex will have antegrade ejaculation in PVS procedures (Sonksen et al., 1994). Factors that inuence the ejaculatory success rate in PVS trials (Table 1) are: (a) the vibrators amplitude (amplitude refers to the peak to peak distance of the moving part of the vibrator (i.e. how far the vibrating part is moving up and down) (Brackett, 1999a) and (b) the level of injury. High-amplitude vibrators yield higher success rates compared with low-amplitude vibrators (54.5% versus 39.9% respectively). In addition, the higher the level of injury the better the ejaculatory success rate of PVS regardless of the type of the vibrator used (high or low amplitude) (Brackett, 1999b). The results of PVS show an overall success rate of ejaculation of 49.8% (Brackett et al., 1998c) or higher (54%) if men injured below T10 are excluded (Nehra et al., 1996). The thoracolumbar emission centre is located between T10 and L3 levels. Thus a higher lesion spares the ejaculatory reex arc. When the level of injury is below T10, PVS may be unsuccessful and rectal probe for electroejaculation should be applied (Nehra et al., 1996). In another study, it has been reported that the majority of patients (seven out 11) with lower lesions (T10L1) have achieved successful retrograde ejaculation with PVS (Brindley, 1981). The quality of sperm specimens recovered using PVS is higher in men (a) with incomplete spinal cord lesions, (b) with higher level of injury and (c) in those voiding without the usage of a catheter as previously suggested by Sonksen et al. (1996). (b) Electroejaculation: The method of rectal electroejaculation was rst described for humans by Learmonth (1931) (Table 1). Until now, many scientists have rened this method and improved its efcacy (Seager & Halstead, 1993). The procedure involves rectal insertion of the electrical probe and positioning of its electrodes in contact with the anterior rectal wall in the area of the prostate gland and the seminal vesicles. One technique of electroejaculation involves the application of electrical stimulations in a wave-like pattern with voltage progressively increasing until ejaculation occurs maintaining between voltage peaks and during ejaculation a low level of electrical current baseline (100 mA) (Sonksen & Ohl, 2002). This method is reported to produce ejaculation after 15 35 stimulations (Ohl et al., 1989). In electroejaculation procedures the patients bladder is catheterised, emptied from the urine and instilled with a
buffer medium appropriate for sperm handling (e.g. Hams F 10 medium) prior to the performance of the electroejaculation procedure. Thus a substantial portion of retrograde ejaculate in this procedure is protected from the inuence of the urine. Rectoscopy is also performed before and after the procedure to ensure that no preexisting lesion or post-procedure injury is present on the rectum. Blood pressure should be monitored for the occurrence of AD and, as in PVS, precautious medication should be administered in high risk patients. Men with partly preserved sensation may experience signicant discomfort and thus require either spinal or general anaesthesia before application of electroejaculation (Ohl et al., 1997; Sonksen & Ohl, 2002). Electroejaculation is successful in producing an antegrade specimen in 63% of men with lower motor neuron lesions (below T10) and in 93% of men with upper motor neuron lesions (above T10) (Momose et al., 1995). Other investigators have reported an overall ejaculatory success rate ranging between 80% and 100% (Warner et al., 1986; Ohl et al., 1989; Nehra et al., 1996; Sonksen & Ohl, 2002). An investigation of the effects of electroejaculation on the quality of recovered spermatozoa demonstrates that retrograde and antegrade ejaculates have decreased sperm viability (510%) and impaired sperm motility (10% and 12% respectively), bovine cervical mucus penetration test outcome and zona free hamster egg penetration assay outcome (Denil et al., 1992). This signicant impairment of sperm motility and viability in the retrograde fraction may be attributed to the presence of urine and a concomitant urine infection (Hirsch et al., 1992). Initially, decreases in sperm motility and viability have been attributed to the electrical current during electroejaculation (Sikka et al., 1994). However, another study has demonstrated no inuence of electrical current on sperm motility (Saito et al., 1999). The effects of the aqueous jelly lubricant used and the heat generated during electroejaculation on sperm motility and viability are insignicant (Linsenmeyer et al., 1989; Witt et al., 1992). Nevertheless some investigators have proved that the electroejaculation method itself may compromise the sperm motility in antegrade ejaculates (Ohl et al., 1997; Yeoman et al., 1998). Both a prospective study in SCI men (Ohl et al., 1997) and in a nonhuman intact spinal cord primate model (Yeoman et al., 1998) have shown signicantly higher values in the sperm motility after PVS than after performance of electroejaculation. A study of the internal and external sphincter response to electroejaculation suggests that electrical stimulation should be paused completely during ejaculation to allow more relaxation of the external sphincter. This approach may reduce the retrograde fraction of the ejaculate (Sonksen et al., 2001).The mean antegrade volume of the
155
Spinal cord injury
ejaculate is signicantly higher with interrupted current delivery versus continuous current delivery. Additionally, the mean retrograde total sperm count is 4-fold higher for the continuous current than for the interrupted current delivery (Brackett et al., 2002). In the total ejaculate of the combined antegrade and retrograde fractions the mean total sperm count and the mean total motile sperm count were not signicantly different by the two methods. It has been recommended by Brackett et al. (2002) to interrupt current delivery when electroejaculation is performed to obtain optimal sperm count for assisted reproductive technology. Comparing the two methods (PVS versus electroejaculation), PVS is simpler to employ, less invasive as no anaesthesia is required, preferred more by patients and yields semen of better quality (Ohl et al., 1997). PVS also has the unique advantage of the possibility of home application. These are the reasons some authors have proposed PVS as rst line treatment when treating anejaculatory men after SCI (Ohl et al., 1997; Brackett, 1999b). Electroejaculation, although it has an amazing 80100% success rate to achieve ejaculation (Ohl et al., 1989; Nehra et al., 1996; Sonksen & Ohl, 2002a,b), is employed when the PVS is not successful. Surgical techniques for sperm recovery If assisted ejaculation procedures fail or yield insufcient number of motile and/or viable spermatozoa for assisted reproductive techniques, surgical procedures for sperm retrieval are indicated along with subsequent assisted reproductive technology methods. Surgical procedures for sperm retrieval include the testicular sperm extraction (TESE) and epididymal or vas deferens spermatozoal aspiration. Some authors have reported successful sperm retrieval from the vas deferens (Chen et al., 1998) and from implanted sperm reservoirs in SCI men (Berger et al., 1986; Brindley et al., 1986; Bustillo & Rajfer, 1986; Macourt et al., 1991). The sperm recovery rate from SCI men ranges from 86% to 100% (Brindley et al., 1986; Hirsh et al., 1993; Dahlberg et al., 1995; Lochner-Ernst et al., 1997). TESE can be applied regardless of the level of lesion, patient age, time period post-injury, hormonal concentrations and semen analysis (Elliott et al., 2000). Proper evaluation of the SCI man is advised prior to the performance of surgical procedures (Lundberg & al, 2000). However, assisted reproduction centres often lack of familiarity, training or equipment regarding PVS and electroejaculation methods and offer intracytoplasmic sperm injection (ICSI) using spermatozoa surgically recovered as the rst line treatment to SCI patients (Kafetsoulis et al., 2006). Even if the surgical techniques for sperm recovery are relatively easy to perform, an
156
effective nonsurgical method is preferable (Linsenmeyer & Perkash, 1991; Kafetsoulis et al., 2006). The contribution of assisted reproductive techniques to the infertility treatment of SCI men Due to the impaired seminal quality, SCI patients usually require assistance for achieving fecundation and consequently, fatherhood. Today, several fertility treatment options are available to enhance the reproduction prospects in SCI men and their partners. Men with adequate semen quality can perform PVS at home and the ejaculate can be used immediately for ovulation-timed vaginal selfinsemination by their partners. The overall pregnancy rates per couple range from 25% to 61% when multiple ovulation cycles have been used to achieve home pregnancies (Dahlberg et al., 1995; Nehra et al., 1996; Lochner-Ernst et al., 1997; Sonksen et al., 1997). When home insemination is ineffective, spermatozoa obtained by PVS or electroejaculation can be used for assisted reproduction techniques such as intrauterine insemination (IUI), in vitro fertilisation (IVF) or ICSI (Borges et al., 1999). Important factors that may inuence the choice of the method to apply are the spermatozoal parameters of the SCI patient, the age and the health condition of his female partner and the procedure costs. Regardless of the way the semen is obtained, spermatozoa can be frozen. Frozen samples can be used as a backup if there is a concern that no spermatozoa will be available on the day of oocyte retrieval (Padron et al., 1994). In IUI, the semen is processed to separate the spermatozoa from the seminal plasma. The concentration of spermatozoa in the ejaculate is a critical factor for the application of this method. IUI is not recommended when the sperm concentration in the ejaculate is below 5 106 ml. The employment of IUI in the therapeutic management of SCI men may be limited by the low motility and low viability of spermatozoa in ejaculates recovered using either PVS or electroejaculation. Delivery rates less than 10% have been reported in IUI programmes in SCI men (Hultling et al., 1997). Other authors, however, state that in SCI patients, more efcient techniques (such as IVF or ICSI) should be offered as the risks and discomfort involved in semen retrieval require employment of methods of assisted reproductive technology that result in higher pregnancy rates than IUI (i.e. either IVF or ICSI) (Hultling et al., 1997). Electroejaculation with stepwise application of assisted reproductive technology is effective in treating anejaculatory infertility. IUI with the least expensive monitoring protocol should be used for most couples, because use of more expensive monitoring did not improve results. It is cost-effective to bypass IUI and proceed directly to IVF in men who require anaesthesia
Spinal cord injury
for electroejaculation and in those with a total inseminated motile sperm count <4 million (Ohl et al., 2001). Intracytoplasmic sperm injection is a feasible alternative option for a patient with SCI in whom IVF has failed (Palermo et al., 1995; Schatte et al., 2000). ICSI consists of the injection of a single spermatozoon into a mature oocyte, with subsequent embryonic transfer to the maternal uterus. ICSI has increased the fertilisation rates in SCI men up to 6088% (Hultling et al., 1997; Schatte et al., 2000), whereas pregnancy rates of approximately 2040% can be achieved (Brinsden et al., 1997; Hultling et al., 1997; Kolettis et al., 2002; Shieh et al., 2003). This means that SCI men with poor sperm quality after SCI or even azoospermic SCI males (Hultling et al., 1997; Schatte et al., 2000) with only a few mature spermatozoa on testicular biopsy minced material or in samples aspirated from the vas deferens (Hovatta & von Smitten, 1993; Tournaye et al., 1996; Schlegel et al., 1997) stand now better chances to become fathers (Hultling et al., 1997; Chung et al., 1998; Schatte et al., 2000). Pregnancy rates after ICSI in SCI men appear to be similar to those obtained in ICSI programmes for male factor infertility without ejaculatory disorders (Carrier et al., 1995; Chung et al., 1998; Schatte et al., 2000). Conclusions Alterations in erectile function, ejaculatory process and male reproductive capacity represent the main andrological consequences of SCI. Recovery of spermatozoa from ejaculates collected via PVS or electroejaculation and employment of methods of assisted reproductive technology give SCI men the possibility to father their own children. If assisted ejaculation procedures fail or yield insufcient number of motile and/or viable spermatozoa for assisted reproductive techniques, surgical procedures for sperm retrieval are indicated along with subsequent assisted reproductive technology methods. References
Adams DB, Victor M (1989) Diseases of the spinal cord. In: Principles of Neurology. Victor M, Ropper RH (eds). McGraw, Hill, New York, pp 718754. Agarwal A, Ikemoto I, Loughlin KR (1994) Effect of sperm washing on levels of reactive oxygen species in semen. Arch Androl 33:157162. Aird IA, Vince GS, Bates MD, Johnson PM, Lewis-Jones ID (1999) Leukocytes in semen from men with spinal cord injuries. Fertil Steril 72:97103. Aitken RJ, Clarkson JS, Fishel S (1989) Generation of reactive oxygen species, lipid peroxidation, and human sperm function. Biol Reprod 41:183197.
Alexandrino AP, Rodrigues MA, Matsuo T (2004) Evaluation of serum and seminal levels of prostate specic antigen in men with spinal cord injury. J Urol 171:2230 2232. Anderson KD, Borisoff JF, Johnson RD, Stiens SA, Elliott SL (2007) Long-term effects of spinal cord injury on sexual function in men: implications for neuroplasticity. Spinal Cord 45:338348. Arafa MM, Zohdy WA, Shamloul R (2007) Prostatic massage: a simple method of semen retrieval in men with spinal cord injury. Int J Androl 30:170173. ASIA (2000) International Standards for Neurological Classications of Spinal Cord Injury (Revised). American Spinal Injury Association, Chicago, pp 123. Aumuller G, Riva A (1992) Morphology and functions of the human seminal vesicle. Andrologia 24:183196. Basu S, Lynne CM, Ruiz P, Aballa TC, Ferrell SM, Brackett NL (2002) Cytouorographic identication of activated T-cell subpopulations in the semen of men with spinal cord injuries. J Androl 23:551556. Basu S, Aballa TC, Ferrell SM, Lynne CM, Brackett NL (2004) Inammatory cytokine concentrations are elevated in seminal plasma of men with spinal cord injuries. J Androl 25:250254. Beattie MS, Leedy MG, Bresnahan JC (1993) Evidence for alterations of synaptic inputs to sacral spinal reex circuits after spinal cord transection in the cat. Exp Neurol 123:3550. Beretta G, Zanollo A, Fanciullacci F, Catanzaro F (1986) Intracavernous injection of papaverine in paraplegic males. Acta Eur Fertil 17:283284. Beretta G, Chelo E, Zanollo A (1989) Reproductive aspects in spinal cord injured males. Paraplegia 27:113118. Berger RE, Muller CH, Smith D, Forster M, Moore D, McIntosh R, Stewart B (1986) Operative recovery of vasal sperm from anejaculatory men: preliminary report. J Urol 135:948950. Biering-Sorensen F, Sonksen J (1992) Penile erection in men with spinal cord or cauda equina lesions. Semin Neurol 12:98105. Biering-Sorensen F, Sonksen J (2001) Sexual function in spinal cord lesioned men. Spinal Cord 39:455470. Billups KL, Tillman SL, Chang TS (1990) Reduction of epididymal sperm motility after ablation of the inferior mesenteric plexus in the rat. Fertil Steril 53:10761082. Blanchard-Dauphin A, Rigot JM, Thevenon A (2005) Treatment of ejaculation disorders by midodrine (Gutron) per os. Retrospective study of about 16 subjects. Ann Readapt Med Phys 48:3440. Blanco R, Saenz de Tejada I, Goldstein I, Krane RJ, Wotiz HH, Cohen RA (1988) Cholinergic neurotransmission in human corpus cavernosum. II. Acetylcholine synthesis. Am J Physiol 254:H468H472. Bodner DR, Lindan R, Lefer E, Kursh ED, Resnick MI (1987) The application of intracavernous injection of vasoactive
157
Spinal cord injury
medications for erection in men with spinal cord injury. J Urol 138:310311. Bodner DR, Haas CA, Krueger B, Seftel AD (1999) Intraurethral alprostadil for treatment of erectile dysfunction in patients with spinal cord injury. Urology 53:199202. Boone TB, Kim ED, Kim Y, al e (1997) Erectile dysfunction and fertility: technical aspects and clinical implications. Adv Rehabil Tech 11:161. Borges EJ, Mori MM, Antunes NJ (1999) Reproducao Assistida e Infertilidade Masculina. In: Consenso Brasileiro Sobre Infertilidade Masculina. Gilma S, Damiao R (ed.). BG Cultural, Sao Paulo, pp 6974. Bors E, Comarr AE (1960) Neurological disturbances of sexual function with special reference to 529 patients with spinal cord injury. Urol Surv 10:191222. Bors E, Engle ET, Rosenquist RC, Holliger VH (1950) Fertility in paraplegic males; a preliminary report of endocrine studies. J Clin Endocrinol Metab 10:381398. Brackett NL (1999a) Penile vibratory stimulation for men with spinal cord injury. Hum Reprod Update 5:551552. Brackett NL (1999b) Semen retrieval by penile vibratory stimulation in men with spinal cord injury. Hum Reprod Update 5:216222. Brackett NL, Lynne CM, Weizman MS, Bloch WE, Abae M (1994a) Endocrine proles and semen quality of spinal cord injured men. J Urol 151:114119. Brackett NL, Lynne CM, Weizman MS, Bloch WE, Padron OF (1994b) Scrotal and oral temperatures are not related to semen quality of serum gonadotropin levels in spinal cordinjured men. J Androl 15:614619. Brackett NL, Abae M, Padron OF, Lynne CM (1995) Treatment by assisted conception of severe male factor infertility due to spinal cord injury or other neurologic impairment. J Assist Reprod Genet 12:210216. Brackett NL, Davi RC, Padron OF, Lynne CM (1996a) Seminal plasma of spinal cord injured men inhibits sperm motility of normal men. J Urol 155:16321635. Brackett NL, Nash MS, Lynne CM (1996b) Male fertility following spinal cord injury: facts and ction. Phys Ther 76:12211231. Brackett NL, Santa-Cruz C, Lynne CM (1997) Sperm from spinal cord injured men lose motility faster than sperm from normal men: the effect is exacerbated at body compared to room temperature. J Urol 157:21502153. Brackett NL, Bloch WE, Lynne CM (1998a) Predictors of necrospermia in men with spinal cord injury. J Urol 159:844847. Brackett NL, Ferrell SM, Aballa TC, Amador MJ, Lynne CM (1998b) Semen quality in spinal cord injured men: does it progressively decline postinjury? Arch Phys Med Rehabil 79:625628. Brackett NL, Ferrell SM, Aballa TC, Amador MJ, Padron OF, Sonksen J, Lynne CM (1998c) An analysis of 653 trials of penile vibratory stimulation in men with spinal cord injury. J Urol 159:19311934.
Brackett NL, Lynne CM, Aballa TC, Ferrell SM (2000) Sperm motility from the vas deferens of spinal cord injured men is higher than from the ejaculate. J Urol 164:712715. Brackett NL, Ead DN, Aballa TC, Ferrell SM, Lynne CM (2002) Semen retrieval in men with spinal cord injury is improved by interrupting current delivery during electroejaculation. J Urol 167:201203. Brackett NL, Cohen DR, Ibrahim E, Aballa TC, Lynne CM (2007a) Neutralization of cytokine activity at the receptor level improves sperm motility in men with spinal cord injuries. J Androl 28:717721. Brackett NL, Kafetsoulis A, Ibrahim E, Aballa TC, Lynne CM (2007b) Application of 2 vibrators salvages ejaculatory failures to 1 vibrator during penile vibratory stimulation in men with spinal cord injuries. J Urol 177:660663. Brackett NL, Ibrahim E, Grotas JA, Aballa TC, Lynne CM (2008) Higher sperm DNA damage in semen from men with spinal cord injuries compared with controls. J Androl 29:93 99; discussion 100101. Brennemann W, Stoffel-Wagner B, Helmers A, Mezger J, Jager N, Klingmuller D (1997) Gonadal function of patients treated with cisplatin based chemotherapy for germ cell cancer. J Urol 158:844850. Brindley GS (1981) Reex ejaculation under vibratory stimulation in paraplegic men. Paraplegia 19:299302. Brindley GS (1982) Deep scrotal temperature and the effect on it of clothing, air temperature, activity, posture and paraplegia. Br J Urol 54:4955. Brindley GS (1988) The Ferrier lecture, 1986. The actions of parasympathetic and sympathetic nerves in human micturition, erection and seminal emission, and their restoration in paraplegic patients by implanted electrical stimulators. Proc R Soc Lond B Biol Sci 235:111120. Brindley GS (1994) The rst 500 patients with sacral anterior root stimulator implants: general description. Paraplegia 32:795805. Brindley GS (1995) Neuroprostheses used to restore male sexual or reproductive function. Baillieres Clin Neurol 4:1520. Brindley GS, Rushton DN (1990) Long-term follow-up of patients with sacral anterior root stimulator implants. Paraplegia 28:469475. Brindley GS, Scott GI, Hendry WF (1986) Vas cannulation with implanted sperm reservoirs for obstructive azoospermia or ejaculatory failure. Br J Urol 58:721723. Brinsden PR, Avery SM, Marcus S, Macnamee MC (1997) Transrectal electroejaculation combined with in-vitro fertilization: effective treatment of anejaculatory infertility due to spinal cord injury. Hum Reprod 12:26872692. Brown DJ, Hill ST, Baker HW (2006) Male fertility and sexual function after spinal cord injury. Prog Brain Res 152:427 439. Buch JP, Kolon TF, Maulik N, Kreutzer DL, Das DK (1994) Cytokines stimulate lipid membrane peroxidation of human sperm. Fertil Steril 62:186188.
158
Spinal cord injury
Burnett AL, Tillman SL, Chang TS, Epstein JI, Lowenstein CJ, Bredt DS, Snyder SH, Walsh PC (1993) Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J Urol 150:7376. Bustillo M, Rajfer J (1986) Pregnancy following insemination with sperm aspirated directly from vas deferens. Fertil Steril 46:144146. Camejo MI, Segnini A, Proverbio F (2001) Interleukin-6 (IL-6) in seminal plasma of infertile men, and lipid peroxidation of their sperm. Arch Androl 47:97101. Carrier S, Zvara P, Nunes L, Kour NW, Rehman J, Lue TF (1995) Regeneration of nitric oxide synthase-containing nerves after cavernous nerve neurotomy in the rat. J Urol 153:17221727. Carro-Juarez M, Cruz SL, Rodriguez-Manzo G (2003) Evidence for the involvement of a spinal pattern generator in the control of the genital motor pattern of ejaculation. Brain Res 975:222228. Celik B, Sahin A, Caglar N, Erhan B, Gunduz B, Gultekin O, Karabulut M (2007) Sex hormone levels and functional outcomes: a controlled study of patients with spinal cord injury compared with healthy subjects. Am J Phys Med Rehabil 86:784790. Chandrashekar V, Bartke A (1992) The inuence of betaendorphin on testicular endocrine function in adult rats. Biol Reprod 47:15. Chao R, Clowers DE (1994) Experience with intracavernosal tri-mixture for the management of neurogenic erectile dysfunction. Arch Phys Med Rehabil 75:276278. Chapelle PA (1983) Pregnancy achieved by ambulatory treatment of anejaculation in the paraplegic man. Apropos of a case. J Urol (Paris) 89:165168. Chapelle PA, Durand J, Lacert P (1980) Penile erection following complete spinal cord injury in man. Br J Urol 52:216 219. Chapelle PA, Blanquart F, Puech AJ, Held JP (1983) Treatment of anejaculation in the total paraplegic by subcutaneous injection of physostigmine. Paraplegia 21:3036. Chapelle PA, Roby-Brami A, Yakovleff A, Bussel B (1988) Neurological correlations of ejaculation and testicular size in men with a complete spinal cord section. J Neurol Neurosurg Psychiatry 51:197202. Chen D, Ling EA, Jeyendran RS (1995) Semen extenders to salvage ejaculate in a retrograde ejaculate environment: a potential use in spinal cord-injured men. Arch Phys Med Rehabil 76:446449. Chen SU, Shieh JY, Wang YH, Chang HC, Ho HN, Yang YS (1998) Pregnancy achieved by intracytoplasmic sperm injection using cryopreserved vasal-epididymal sperm from a man with spinal cord injury. Arch Phys Med Rehabil 79:218 221. Chuang AT, Steers WD (1999) Neurophysiology of penile erection. In: Textbook of Erection Dysfunction. Carson C, Kirby R, Goldstein I (eds). ISIS Medical Media Inc, Oxford, UK, pp 5972.
Chung PH, Palermo G, Schlegel PN, Veeck LL, Eid JF, Rosenwaks Z (1998) The use of intracytoplasmic sperm injection with electroejaculates from anejaculatory men. Hum Reprod 13:18541858. Cohen DR, Basu S, Randall JM, Aballa TC, Lynne CM, Brackett NL (2004) Sperm motility in men with spinal cord injuries is enhanced by inactivating cytokines in the seminal plasma. J Androl 25:922925. Comarr AE (1970) Sexual function among patients with spinal cord injury. Urol Int 25:134168. Courtois F, Geoffrion R, Landry E, Belanger M (2004) H-reex and physiologic measures of ejaculation in men with spinal cord injury. Arch Phys Med Rehabil 85:910918. Dahlberg A, Ruutu M, Hovatta O (1995) Pregnancy results from a vibrator application, electroejaculation, and a vas aspiration programme in spinal-cord injured men. Hum Reprod 10:23052307. Das S, Dodd S, Soni BM, Sharma SD, Gazvani R, LewisJones DI (2006) Does repeated electro-ejaculation improve sperm quality in spinal cord injured men? Spinal Cord 44:753756. Dashtdar H, Valojerdi MR (2008) Ultrastructure of rat seminal vesicle epithelium in the acute phase of spinal cord transection. Neurol Res 30: 487492. DeGroat WC, Booth AM (1993) Neural control of penile erection. In: The Autonomic Nervous System Nervous Control of The Urogenital System Chap 13. Maggi CA (ed). Harwood, London, pp 465513. Del Popolo G, Li Marzi V, Mondaini N, Lombardi G (2004) Time/duration effectiveness of sildenal versus tadalal in the treatment of erectile dysfunction in male spinal cordinjured patients. Spinal Cord 42:643648. el-Demiry M, James K (1988) Lymphocyte subsets and macrophages in the male genital tract in health and disease. A monoclonal antibody-based study. Eur Urol 14:226235. Denil J, Ohl DA, Menge AC, Keller LM, McCabe M (1992) Functional characteristics of sperm obtained by electroejaculation. J Urol 147:6972. Denil J, Ohl DA, Smythe C (1996) Vacuum erection device in spinal cord injured men: patient and partner satisfaction. Arch Phys Med Rehabil 77:750753. Denys P, Mane M, Azouvi P, Chartier-Kastler E, Thiebaut JB, Bussel B (1998) Side effects of chronic intrathecal baclofen on erection and ejaculation in patients with spinal cord lesions. Arch Phys Med Rehabil 79:494496. Derry FA, Dinsmore WW, Fraser M, Gardner BP, Glass CA, Maytom MC, Smith MD (1998) Efcacy and safety of oral sildenal (Viagra) in men with erectile dysfunction caused by spinal cord injury. Neurology 51:16291633. Dietzen CJ, Lloyd LK (1992) Complications of intracavernous injections and penile prostheses in spinal cord injured men. Arch Phys Med Rehabil 73:652655. Donohue J, Gebhard P (1995) The Kinsey Institute/Indiana University report on sexual and spinal cord injury. Sex Disabil 13:784.
159
Spinal cord injury
Earle CM, Keogh EJ, Ker JK, Cherry DJ, Tulloch AG, Lord DJ (1992) The role of intracavernosal vasoactive agents to overcome impotence due to spinal cord injury. Paraplegia 30:273276. Eid JF (1992) Electroejaculation. AUA Update Series 11 Elliott S (2003) Sexual dysfunction and infertility in men with spinal cord disorders. In: Spinal Cord Medicine: Principles and Practice. Lin V (ed). Demos Medical Publishing, New York, pp 350365. Elliott SL (2006) Problems of sexual function after spinal cord injury. Prog Brain Res 152:387399. Elliott S, Krassioukov A (2006) Malignant autonomic dysreflexia in spinal cord injured men. Spinal Cord 44:386392. Elliott SP, Orejuela F, Hirsch IH, Lipshultz LI, Lamb DJ, Kim ED (2000) Testis biopsy ndings in the spinal cord injured patient. J Urol 163:792795. Engh E, Clausen OP, Purvis K, Stien R (1993) Sperm quality assessed by ow cytometry and accessory sex gland function in spinal cord injured men after repeated vibration-induced ejaculation. Paraplegia 31:312. Fabbri A, Knox G, Buczko E, Dufau ML (1988) Beta-endorphin production by the fetal Leydig cell: regulation and implications for paracrine control of Sertoli cell function. Endocrinology 122:749755. Fahmy I, Kamal A, Metwali M, Rhodes C, Mansour R, Serour G, Aboulghar M (1999) Vigorous prostatic massage: a simple method to retrieve spermatozoa for intracytoplasmic sperm injection in psychogenic anejaculation: case report. Hum Reprod 14:20502053. Francois N, Jouannet P, Maury M (1983) Genitosexual function of paraplegics. J Urol (Paris) 89:159164. Fukuda A, Roudebush WE, Thatcher SS (1994) Platelet activating factor enhances the acrosome reaction, fertilization in vitro by subzonal sperm injection and resulting embryonic development in the rabbit. Hum Reprod 9:9499. Giagulli VA, Vermeulen A (1988) Leydig cell function in infertile men with idiopathic oligospermic infertility. J Clin Endocrinol Metab 66:6267. Giuliano F, Hultling C, El Masry WS, Smith MD, Osterloh IH, Orr M, Maytom M (1999) Randomized trial of sildenal for the treatment of erectile dysfunction in spinal cord injury. Sildenal Study Group. Ann Neurol 46:1521. Giuliano F, Rubio-Aurioles E, Kennelly M, Montorsi F, Kim ED, Finkbeiner AE, Pommerville PJ, Colopy MW, Wilkins HJ, Wachs BH (2006) Efcacy and safety of vardenal in men with erectile dysfunction caused by spinal cord injury. Neurology 66:210216. Giuliano F, Sanchez-Ramos A, Lochner-Ernst D, Del Popolo G, Cruz N, Leriche A, Lombardi G, Reichert S, Dahl P, Elion-Mboussa A, Casariego J (2007) Efcacy and safety of tadalal in men with erectile dysfunction following spinal cord injury. Arch Neurol 64:15841592. Golji H (1979) Experience with penile prosthesis in spinal cord injury patients. J Urol 121:288289.
Gonzales GF, Kortebani G, Mazzolli AB (1992) Leukocytospermia and function of the seminal vesicles on seminal quality. Fertil Steril 57:10581065. Grifth ER, Tomko MA, Timms RJ (1973) Sexual function in spinal cord-injured patients: a review. Arch Phys Med Rehabil 54:539543. Guly HR, Bouamra O, Lecky FE (2008) The incidence of neurogenic shock in patients with isolated spinal cord injury in the emergency department. Resuscitation 76:5762. Guttmann L (1976) The sexual problem. In: Spinal Cord Injuries Comprehensive Management and Research. Osney M (ed). Blackwell Scientic Publications, Oxford, London, Edinburgh, Melbourne, pp 474505. Guttmann L, Walsh JJ (1971) Prostigmin assessment test of fertility in spinal man. Paraplegia 9:3951. Guttmann L, Whitteridge D (1947) Effects of bladder distension on autonomic mechanisms after spinal cord injuries. Brain 70:361404. Halata Z, Munger BL (1986) The neuroanatomical basis for the protopathic sensibility of the human glans penis. Brain Res 371:205230. Halstead LS, VerVoort S, Seager SW (1987) Rectal probe electrostimulation in the treatment of anejaculatory spinal cord injured men. Paraplegia 25:120129. Harrison PE, Barratt CL, Robinson AJ, Kessopoulou E, Cooke ID (1991) Detection of white blood cell populations in the ejaculates of fertile men. J Reprod Immunol 19:9598. Heinline UI, Chang C (2002) The role of androgen receptors and androgen binding proteins in nongenomic androgen actions. Mol Endocrinol 16:21812187. Hellstrom WJ, Stone AR, Deitch AD, deVere White RW (1989) The clinical application of aspiration deoxyribonucleic acid ow cytometry to neurologically impaired men entering an electroejaculation program. J Urol 142:309 312. Hill JA, Haimovici F, Politch JA, Anderson DJ (1987) Effects of soluble products of activated lymphocytes and macrophages (lymphokines and monokines) on human sperm motion parameters. Fertil Steril 47:460465. Hirsch IH, Jeyendran RS, Sedor J, Rosecrans RR, Staas WE (1991a) Biochemical analysis of electroejaculates in spinal cord injured men: comparison to normal ejaculates. J Urol 145:7376. Hirsch IH, McCue P, Allen J, Lee J, Staas WE (1991b) Quantitative testicular biopsy in spinal cord injured men: comparison to fertile controls. J Urol 146:337341. Hirsch IH, Sedor J, Jeyendran RS, Staas WE (1992) The relative distribution of viable sperm in the antegrade and retrograde portions of ejaculates obtained after electrostimulation. Fertil Steril 57:399401. Hirsch IH, Smith RL, Chancellor MB, Bagley DH, Carsello J, Staas WE Jr (1994) Use of intracavernous injection of prostaglandin E1 for neuropathic erectile dysfunction. Paraplegia 32:661664.
160
Spinal cord injury
Hirsch IH, Huang B, Chancellor MB, Rivas DA, Salzman SK, Jost LK, Evenson DP (1999) Spermatogenesis in early and chronic phases of experimental spinal cord injury in the rodent model. J Androl 20:6371. Hirsh AV, Mills C, Tan SL, Bekir J, Rainsbury P (1993) Pregnancy using spermatozoa aspirated from the vas deferens in a patient with ejaculatory failure due to spinal injury. Hum Reprod 8:8990. Holmes GM, Chapple WD, Leipheimer RE, Sachs BD (1991) Electromyographic analysis of male rat perineal muscles during copulation and reexive erections. Physiol Behav 49:12351246. Holstein AF, Sauerwein D, Schirren U (1985) Spermatogenesis in patients with traumatic transverse paralysis. Urologe A 24:208215. Hou JW, Chen D, Jeyendran RS (1995) Sperm nuclear maturity in spinal cord-injured men: evaluation by acidic aniline blue stain. Arch Phys Med Rehabil 76:444445. Hovatta O, von Smitten K (1993) Sperm aspiration from vas deferens and in-vitro fertilization in cases of non-treatable anejaculation. Hum Reprod 8:16891691. Hovav Y, Kafka I, Horenstein E, Yaffe H (2000) Prostatic massage as a method for obtaining spermatozoa in men with psychogenic anejaculation. Fertil Steril 74:184185. Huang HF, Linsenmeyer TA, Li MT, Giglio W, Anesetti R, von Hagen J, Ottenweller JE, Serenas C, Pogach L (1995) Acute effects of spinal cord injury on the pituitarytesticular hormone axis and Sertoli cell functions: a time course study. J Androl 16:148157. Huang HF, Li MT, Linsenmeyer TA, Ottenweller JE, Pogach LM, Irwin RJ (1997) The effects of spinal cord injury on the status of messenger ribonucleic acid for TRPM 2 and androgen receptor in the prostate of the rat. J Androl 18:250256. Huang HF, Linsenmeyer TA, Anesetti R, Giglio W, Ottenweller JE, Pogach L (1998) Suppression and recovery of spermatogenesis following spinal cord injury in the rat. J Androl 19:7280. Huang HF, Li MT, Anesetti R, Giglio W, Ottenweller JE, Pogach LM (1999a) Effects of spinal cord injury on spermatogenesis and the expression of messenger ribonucleic acid for Sertoli cell proteins in rat Sertoli cell-enriched testes. Biol Reprod 60:635641. Huang HF, Li MT, Giglio W, Anesetti R, Ottenweller JE, Pogach LM (1999b) The detrimental effects of spinal cord injury on spermatogenesis in the rat is partially reversed by testosterone, but enhanced by follicle-stimulating hormone. Endocrinology 140:13491355. Huang HF, Li MT, Wang S, Wang G, Ottenweller JE (2003) Spinal cord contusion impairs sperm motility in the rat without disrupting spermatogenesis. J Androl 24:371 380. Huang HF, Wang S, Molina CA, Ottenweller JE (2004) Preservation of spermatogenesis in spinal cord injured rats with exogenous testosterone. Relationship with serum
testosterone levels and cellular localization of cAMP responsive element modulator. J Androl 25:95103. Huang TS, Wang YH, Chiang HS, Lien YN (1993) Pituitary testicular and pituitarythyroid axes in spinal cord-injured males. Metabolism 42:516521. Hultling C, Rosenlund B, Levi R, Fridstrom M, Sjoblom P, Hillensjo T (1997) Assisted ejaculation and in-vitro fertilization in the treatment of infertile spinal cord-injured men: the role of intracytoplasmic sperm injection. Hum Reprod 12:499502. Hvarness H, Jakobsen H, Biering-Sorensen F (2007) Men with spinal cord injury have a smaller prostate than men without. Scand J Urol Nephrol 41:120123. Jesionowska H, Hemmings R (1991) Good-quality semen recovered from a paraplegic man with physostigmine salicylate treatment. A case report. J Reprod Med 36:167169. Jeulin C, Sour JC, Weber P, Laval-Martin D, Calvayrac R (1989) Catalase activity in human spermatozoa and seminal plasma. Gamete Res 24:185196. Johnson RD (1988) Efferent modulation of penile mechanoreceptor activity. Prog Brain Res 74:319324. Johnson RD, Halata Z (1991) Topography and ultrastructure of sensory nerve endings in the glans penis of the rat. J Comp Neurol 312:299310. Johnson RD, Hubscher CH (1998) Brainstem microstimulation differentially inhibits pudendal motoneuron reex inputs. Neuroreport 9:341345. Johnson RD, Murray FT (1992) Reduced sensitivity of penile mechanoreceptors in aging rats with sexual dysfunction. Brain Res Bull 28:6164. Juenemann KP, Alken P (1989) Pharmacotherapy of erectile dysfunction: a review. Int J Impot Res 1:7193. Kabalin JN, Kessler R (1988) Infectious complications of penile prosthesis surgery. J Urol 139:953955. Kafetsoulis A, Brackett NL, Ibrahim E, Attia GR, Lynne CM (2006) Current trends in the treatment of infertility in men with spinal cord injury. Fertil Steril 86:781789. Kapoor VK, Chahal AS, Jyoti SP, Mundkur YJ, Kotwal SV, Mehta VK (1993) Intracavernous papaverine for impotence in spinal cord injured patients. Paraplegia 31:675677. Kikuchi TA, Skowsky WR, El-Toraei I, Swerdloff R (1976) The pituitarygonadal axis in spinal cord injury. Fertil Steril 27:11421145. Kim ED, McVary KT (1995) Topical prostaglandin-E1 for the treatment of erectile dysfunction. J Urol 153:18281830. Kim ED, el-Rashidy R, McVary KT (1995) Papaverine topical gel for treatment of erectile dysfunction. J Urol 153:361365. Kise H, Nishioka J, Kawamura J, Suzuki K (1996) Characterization of semenogelin II and its molecular interaction with prostate-specic antigen and protein C inhibitor. Eur J Biochem 238:8896. Ko HY, Ditunno JF Jr, Graziani V, Little JW (1999) The pattern of reex recovery during spinal shock. Spinal Cord 37:402409.
161
Spinal cord injury
Kolettis PN, Lambert MC, Hammond KR, Kretzer PA, Steinkampf MP, Lloyd LK (2002) Fertility outcomes after electroejaculation in men with spinal cord injury. Fertil Steril 78:429431. Kuhn RA (1950) Functional capacity of the isolated human spinal cord. Brain 73:151. de Lamirande E, Gagnon C (1992) Reactive oxygen species and human spermatozoa. I. Effects on the motility of intact spermatozoa and on sperm axonemes. J Androl 13:368378. de Lamirande E, Leduc BE, Iwasaki A, Hassouna M, Gagnon C (1995) Increased reactive oxygen species formation in semen of patients with spinal cord injury. Fertil Steril 63:637642. Larsen E, Hejgaard N (1984) Sexual dysfunction after spinal cord or cauda equina lesions. Paraplegia 22:6674. Le Chapelain L, Nguyen van Tam P, Dehail P, Berjon JJ, Barat M, Mazaux JM, Joseph PA (1998) Ejaculatory stimulation, quality of semen and reproductive aspects in spinal cord injured men. Spinal Cord 36:132136. Learmonth JR (1931) A contribution to the neurophysiology of the urinary bladder in man. Brain 54:147176. Lee S, Miselis R, Rivier C (2002) Anatomical and functional evidence for a neural hypothalamic-testicular pathway that is independent of the pituitary. Endocrinology 143:4447 4454. Leriche A, Berard E, Vauzelle JL, Minaire P, Girard R, Archimbaud JP, Bourret J (1977) Histological and hormonal testicular changes in spinal cord patients. Paraplegia 15:274 279. Levin RM, Wein AJ (1980) Adrenergic alpha receptors outnumber beta receptors in human penile corpus cavernosum. Invest Urol 18:225226. Lilja H, Lundwall A (1992) Molecular cloning of epididymal and seminal vesicular transcripts encoding a semenogelinrelated protein. Proc Natl Acad Sci U S A 89:45594563. Linsenmeyer TA, Perkash I (1991) Infertility in men with spinal cord injury. Arch Phys Med Rehabil 72:747754. Linsenmeyer T, Wilmot C, Anderson RU (1989) The effects of the electroejaculation procedure on sperm motility. Paraplegia 27:465469. Linsenmeyer TA, Pogach LM, Ottenweller JE, Huang HF (1994) Spermatogenesis and the pituitarytesticular hormone axis in rats during the acute phase of spinal cord injury. J Urol 152:13021307. Lloyd EE, Toth LL, Perkash I (1989) Vacuum tumescence: an option for spinal cord injured males with erectile dysfunction. SCI Nurs 6:2528. Lochner-Ernst D, Mandalka B, Kramer G, Stohrer M (1997) Conservative and surgical semen retrieval in patients with spinal cord injury. Spinal Cord 35:463468. Lopez GJ, Kollar WC (2000) Sexual function, dysfunction, orientation and the autonomic nervous system. In: Handbook of Clinical Neurology The Autonomic Nervous System, Part II Dysfunctions Chapter 3. Appenzeller O (ed). Elsevier, Amsterdam, pp 85103.
Lundberg PO, al e (2000) Neurological disorders: erectile and ejaculatory dysfunction. In: Erectile Dysfunction. Jardin A, Wagner G, Khoury S, Giuliano F, Padma-Nathan H, Rosen R (eds). Health Publication Ltd, UK, pp 591645. Lynne CM, Aballa TC, Wang TJ, Rittenhouse HG, Ferrell SM, Brackett NL (1999) Serum and semen prostate specic antigen concentrations are different in young spinal cord injured men compared to normal controls. J Urol 162:89 91. Macourt D, Engel S, Jones RF, Zaki M (1991) Pregnancy by gamete intrafallopian transfer (GIFT) with sperm aspirated from the vaso-epididymal junction of spinal injured man: case report. Paraplegia 29:550553. Mallidis C, Lim TC, Hill ST, Skinner DJ, Brown DJ, Johnston WI, Baker HW (1994) Collection of semen from men in acute phase of spinal cord injury. Lancet 343:10721073. Marina S, Marina F, Alcolea R, Nadal J, Pons MC, Grossmann M, Exposito R, Vidal J (1999) Triplet pregnancy achieved through intracytoplasmic sperm injection with spermatozoa obtained by prostatic massage of a paraplegic patient: case report. Hum Reprod 14:15461548. Maytom MC, Derry FA, Dinsmore WW, Glass CA, Smith MD, Orr M, Osterloh IH (1999) A two-part pilot study of sildenal (VIAGRA) in men with erectile dysfunction caused by spinal cord injury. Spinal Cord 37:110116. McBride F, Quah SP, Scott ME, Dinsmore WW (2003) Tripling of blood pressure by sexual stimulation in a man with spinal cord injury. J R Soc Med 96:349350. McKenna K (1999) The brain is the master organ in sexual function: Central nervous system control of male and female sexual function. Int J Impot Res II (Suppl 11):S48S55. McKenna KE, Nadelhaft I (1989) The pudendo-pudendal reex in male and female rats. J Auton Nerv Syst 27:67 77. McKenna KE, Chung SK, McVary KT (1991) A model for the study of sexual function in anesthetized male and female rats. Am J Physiol 261:R1276R1285. Means AR, Fakunding JL, Huckins C, Tindall DJ, Vitale R (1976) Follicle-stimulating hormone, the Sertoli cell, and spermatogenesis. Recent Prog Horm Res 32:477527. Meisel RL, Sachs BD (1994) The physiology of male sexual behavior. In: The Physiology of Reproduction. Knobil E, Neill JDD (eds). Raven Press, New York, pp 3105. Melman A, Rehman J (1999) Pathophysiology of erectile dysfunction. Mol Urol 3:87102. Melman A, Henry DP, Felten DL, OConnor BL (1980) Alteration of the penile corpora in patients with erectile impotence. Invest Urol 17:474477. Miesel R, Weser U (1991) Chemiluminescence assays of Cu2Zn2 superoxide dismutase mimicking Cu-complexes. Free Radic Res Commun 12-13 (Pt 1):253258. Momen MN, Fahmy I, Amer M, Arafa M, Zohdy W, Naser TA (2007) Semen parameters in men with spinal cord injury: changes and aetiology. Asian J Androl 9:684689.
162
Spinal cord injury
Momose H, Hirao Y, Yamamoto M, Yamada K, Okajima E (1995) Electroejaculation in patients with spinal cord injury: rst report of a large-scale experience from Japan. Int J Urol 2:326329. Monga M, Bernie J, Rajasekaran M (1999) Male infertility and erectile dysfunction in spinal cord injury: a review. Arch Phys Med Rehabil 80:13311339. Morris PL, Vale WW, Bardin CW (1987) Beta-endorphin regulation of FSH-stimulated inhibin production is a component of a short loop system in testis. Biochem Biophys Res Commun 148:15131519. Nacimiento W, Noth J (1999) What, if anything, is spinal shock? Arch Neurol 56:10331035. Nadelhaft I, McKenna KE (1987) Sexual dimorphism in sympathetic preganglionic neurons of the rat hypogastric nerve. J Comp Neurol 256:308315. Naderi AR, Safarinejad MR (2003) Endocrine proles and semen quality in spinal cord injured men. Clin Endocrinol (Oxf) 58:177184. Nehra A, Werner MA, Bastuba M, Title C, Oates RD (1996) Vibratory stimulation and rectal probe electroejaculation as therapy for patients with spinal cord injury: semen parameters and pregnancy rates. J Urol 155:554559. Odeh AI, Dascanio JJ, Caceci T, Bowen J, Eng LA (2003) Effect of platelet-activating factor (PAF) on stallion sperm motility, capacitation and the acrosome reaction. Reproduction 126:605613. Ohl DA, Sonksen J (1996) Sperm collection for assisted reproduction in ejaculatory dysfunctions. In: Human Spermatozoa in Assisted Reproduction. Acosta AA, Kruger TF (eds). Parthenon Publishing, Carnforth, pp 455472. Ohl DA, Bennett CJ, McCabe M, Menge AC, McGuire EJ (1989) Predictors of success in electroejaculation of spinal cord injured men. J Urol 142:14831486. Ohl DA, Sonksen J, Menge AC, McCabe M, Keller LM (1997) Electroejaculation versus vibratory stimulation in spinal cord injured men: sperm quality and patient preference. J Urol 157:21472149. Ohl DA, Menge AC, Jarow JP (1999) Seminal vesicle aspiration in spinal cord injured men: insight into poor sperm quality. J Urol 162:20482051. Ohl DA, Sonksen J, Wedemeyer G, Zaborniak MC, Dam TN, Menge AC, Putzi MJ, Papadopoulos SM (2001) Canine model of infertility after spinal cord injury: time course of acute changes in semen quality and spermatogenesis. J Urol 166:11811184. Okada H, Fujisawa M, Koshida M, Kamidono S (2001) Ampullary, seminal vesicular, and prostatic massage for obtaining spermatozoa from patients with anejaculation. Fertil Steril 75:12361237. Ottenweller JE, Li MT, Giglio W, Anesetti R, Pogach LM, Huang HF (2000) Alteration of follicle-stimulating hormone and testosterone regulation of messenger ribonucleic acid for Sertoli cell proteins in the rat during the acute phase of spinal cord injury. Biol Reprod 63:730735.
Padron OF, Brackett NL, Weizman MS, Lynne CM (1994) Semen of spinal cord injured men freezes reliably. J Androl 15:266269. Padron OF, Brackett NL, Sharma RK, Lynne CM, Thomas AJ Jr, Agarwal A (1997) Seminal reactive oxygen species and sperm motility and morphology in men with spinal cord injury. Fertil Steril 67:11151120. Palermo GD, Cohen J, Alikani M, Adler A, Rosenwaks Z (1995) Intracytoplasmic sperm injection: a novel treatment for all forms of male factor infertility. Fertil Steril 63:1231 1240. Pandya IJ, Cohen J (1985) The leukocytic reaction of the human uterine cervix to spermatozoa. Fertil Steril 43:417 421. Peehl DM (1996) Cellular biology of prostatic growth factors. Prostate 29 (Suppl 6):7478. Perkash I, Martin DE, Warner H, Blank MS, Collins DC (1985) Reproductive biology of paraplegics: results of semen collection, testicular biopsy and serum hormone evaluation. J Urol 134:284288. Piera JB (1973) The establishment of a prognosis for genitosexual function in the paraplegic and tetraplegic male. Paraplegia 10:271278. Plymate SR, Rosen CJ, Paulsen CA, Ware JL, Chen J, Vessella RE, Birnbaum RS (1996) Proteolysis of insulin-like growth factor-binding protein-3 in the male reproductive tract. J Clin Endocrinol Metab 81:618624. Prakash V, Lin MS, Song CH, Perkash I (1980) Thyroid hypofunction in spinal cord injury patients. Paraplegia 18:5663. Rajasekaran M, Hellstrom WJ, Naz RK, Sikka SC (1995) Oxidative stress and interleukins in seminal plasma during leukocytospermia. Fertil Steril 64:166171. Randall MJ, Evans HD, Bird GV, Aballa CT, Lynne MC, Bracket LN (2003) Leukocytospermia in spinal cord injured patients is not related to histological inammatory changes in the prostate. J Urol 170:897900. Rawicki HB, Hill S (1991) Semen retrieval in spinal cord injured men. Paraplegia 29:443446. Ricker DD, Minhas BS, Kumar R, Robertson JL, Dodson MG (1989) The effects of platelet-activating factor on the motility of human spermatozoa. Fertil Steril 52:655658. Riley AJ, Riley EJ (1982) Partial ejaculatory incompetence: the therapeutic effect of midodrine, an orally active selective alpha-adrenoceptor agonist. Eur Urol 8:155160. Robertson SA, Ingman WV, OLeary S, Sharkey DJ, Tremellen KP (2002) Transforming growth factor beta a mediator of immune deviation in seminal plasma. J Reprod Immunol 57:109128. Rossier AB, Fam BA (1984) Indication and results of semirigid penile prostheses in spinal cord injury patients: long-term followup. J Urol 131:5962. Russo P, Warner JA, Huryk R, Perez G, Heston WD (1994) TRPM-2 gene expression in normal rat ventral prostate following castration and exposure to diethylstilbestrol,
163
Spinal cord injury
utamide, MK-906 (nasteride), and coumarin. Prostate 24:237243. Saez JM (1994) Leydig cells: endocrine, paracrine, and autocrine regulation. Endocr Rev 15:574626. Saito K, Kinoshita Y, Hosaka M (1999) Direct and indirect effects of electrical stimulation on the motility of human sperm. Int J Urol 6:196199. Sassone-Corsi P (1998) CREM: a master-switch governing male germ cells differentiation and apoptosis. Semin Cell Dev Biol 9:475482. Schatte EC, Orejuela FJ, Lipshultz LI, Kim ED, Lamb DJ (2000) Treatment of infertility due to anejaculation in the male with electroejaculation and intracytoplasmic sperm injection. J Urol 163:17171720. Schlegel PN, Palermo GD, Goldstein M, Menendez S, Zaninovic N, Veeck LL, Rosenwaks Z (1997) Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia. Urology 49:435440. Schmid DM, Schurch B, Hauri D (2000) Sildenal in the treatment of sexual dysfunction in spinal cord-injured male patients. Eur Urol 38:184193. Schmidt MH, Schmidt HS (1993) The ischiocavernosus and bulbospongiosus muscles in mammalian penile rigidity. Sleep 16:171183. Schroder HD (1985) Anatomical and pathoanatomical studies on the spinal efferent systems innervating pelvic structures. 1. Organization of spinal nuclei in animals. 2. The nucleus X-pelvic motor system in man. J Auton Nerv Syst 14:2348. Schultheiss D, Stief CG (1999) Physiology and pathophysiology of erection: consequences for present medical therapy of erectile dysfunction. Andrologia 31(Suppl 1):5964. Schwale M, Frosch P, Tolle E, Niermann H (1980) Treatment of retrograde ejaculation and anorgasm with an alphasympathomimetic agent (Midodrin). Z Hautkr 55:756759. Seager SW, Halstead LS (1993) Fertility options and success after spinal cord injury. Urol Clin North Am 20:543548. Sedor JF, Hirsch IH (1995) Evaluation of sperm morphology of electroejaculates of spinal cord-injured men by strict criteria. Fertil Steril 63:11251127. Sengoku K, Tamate K, Takaoka Y, Ishikawa M (1993) Effects of platelet activating factor on human sperm function in vitro. Hum Reprod 8:14431447. Sharma RK, Agarwal A (1996) Role of reactive oxygen species in male infertility. Urology 48:835850. Sheel AW, Krassioukov AV, Inglis JT, Elliott SL (2005) Autonomic dysreexia during sperm retrieval in spinal cord injury: inuence of lesion level and sildenal citrate. J Appl Physiol 99:5358. Shieh JY, Chen SU, Wang YH, Chang HC, Ho HN, Yang YS (2003) A protocol of electroejaculation and systematic assisted reproductive technology achieved high efciency and efcacy for pregnancy for anejaculatory men with spinal cord injury. Arch Phys Med Rehabil 84:535540. Shirai M, Sasaki K, Rikimaru A (1973) A histochemical investigation of the distribution of adrenergic and cholinergic
nerves in the human male genital organs. Tohoku J Exp Med 111:281291. Sidi AA, Cameron JS, Duffy LM, Lange PH (1986) Intracavernous drug-induced erections in the management of male erectile dysfunction: experience with 100 patients. J Urol 135:704706. Sidi AA, Cameron JS, Dykstra DD, Reinberg Y, Lange PH (1987) Vasoactive intracavernous pharmacotherapy for the treatment of erectile impotence in men with spinal cord injury. J Urol 138:539542. Sikka SC, Wang R, Kukuy E, Walker CF, Hellstrom WJ (1994) The detrimental effects of electric current on normal human sperm. J Androl 15:145150. Siosteen A, Lundqvist C, Blomstrand C, Sullivan L, Sullivan M (1990) Sexual ability, activity, attitudes and satisfaction as part of adjustment in spinal cord-injured subjects. Paraplegia 28:285295. Sipski ML (1991) The impact of spinal cord injury on female sexuality, menstruation and pregnancy: a review of the literature. J Am Paraplegia Soc 14:122126. Slot O, Drewes A, Andreasen A, Olsson A (1989) Erectile and ejaculatory function of males with spinal cord injury. Int Disabil Stud 11:7577. Sobrero AJ, Stearns HE, Blair JH (1965) Technic for the induction of ejaculation in humans. Fertil Steril 16:765767. Sokitis NV, Miyagawa I (1993) Endocrinological, biophysical, and biochemical parameters of semen collected via masturbation versus sexual intercourse. J Androl 14:366373. Soler JM (2005) Treatment of ejaculation disorders. Ann Readapt Med Phys 48:4142. Soler JM, Previnaire JG, Plante P, Denys P, Chartier-Kastler E (2007) Midodrine improves ejaculation in spinal cord injured men. J Urol 178:20822086. Sonksen J, Biering-Sorensen F (1992) Transcutaneous nitroglycerin in the treatment of erectile dysfunction in spinal cord injured. Paraplegia 30:554557. Sonksen J, Ohl DA (2002) Penile vibratory stimulation and electroejaculation in the treatment of ejaculatory dysfunction. Int J Androl 25:324332. Sonksen JO, Hansen EF, Biering-Sorensen F, Colstrup H (1990) Intracavernous self-injection for treatment of erectile dysfunction inpatients with spinal cord injuries. Ugeskr Laeger 152:30063009. Sonksen J, Biering-Sorensen F, Kristensen JK (1994) Ejaculation induced by penile vibratory stimulation in men with spinal cord injuries. The importance of the vibratory amplitude. Paraplegia 32:651660. Sonksen J, Ohl DA, Giwercman A, Biering-Sorensen F, Kristensen JK (1996) Quality of semen obtained by penile vibratory stimulation in men with spinal cord injuries: observations and predictors. Urology 48:453457. Sonksen J, Sommer P, Biering-Sorensen F, Ziebe S, Lindhard A, Loft A, Andersen AN, Kristensen JK (1997) Pregnancy after assisted ejaculation procedures in men with spinal cord injury. Arch Phys Med Rehabil 78:10591061.
164
Spinal cord injury
Sonksen J, Ohl DA, Giwercman A, Biering-Sorensen F, Skakkebaek NE, Kristensen JK (1999) Effect of repeated ejaculation on semen quality in spinal cord injured men. J Urol 161:11631165. Sonksen J, Ohl DA, Wedemeyer G (2001) Sphincteric events during penile vibratory ejaculation and electroejaculation in men with spinal cord injuries. J Urol 165:426429. Staerman F, Bryckaert PE, Youinou Y, Colin J, Brandt B, Lardennois B (2001) Pharmacologic stimulation of ejaculation with midodrine hydrochloride (Gutron) for medically assisted reproduction in spinal injury. Prog Urol 11:12641268. Stemmermann GN, Weiss L, Auerbach O, Friedman M (1950) A study of the germinal epithelium in male paraplegics. Am J Clin Pathol 20:2434, illust. Szasz G (1986) Sexual function in the spinal cord injured. In: Management of Spinal Cord Injuries. Bloch RF, Basbaum M (eds). pp 439455. Williams and Wilkins, Baltimore Szasz G, Carpenter C (1989) Clinical observations in vibratory stimulation of the penis of men with spinal cord injury. Arch Sex Behav 18:461474. Takao T, Mitchell WM, Tracey DE, De Souza EB (1990) Identication of interleukin-1 receptors in mouse testis. Endocrinology 127:251258. Talebi AR, Khalili MA, Hossaini A (2007) Assessment of nuclear DNA integrity of epididymal spermatozoa following experimental chronic spinal cord injury in the rat. Int J Androl 30:163169. Teasell RW, Arnold JM, Krassioukov A, Delaney GA (2000) Cardiovascular consequences of loss of supraspinal control of the sympathetic nervous system after spinal cord injury. Arch Phys Med Rehabil 81:506516. Tournaye H, Liu J, Nagy PZ, Camus M, Goossens A, Silber S, van Steirteghem AC, Devroey P (1996) Correlation between testicular histology and outcome after intracytoplasmic sperm injection using testicular spermatozoa. Hum Reprod 11:127132. Trabulsi EJ, Shupp-Byrne D, Sedor J, Hirsch IH (2002) Leukocyte subtypes in electroejaculates of spinal cord injured men. Arch Phys Med Rehabil 83:3134. Tsuji I, Nakajima F, Morimoto J, Nounaka Y (1961) The sexual function in patients with spinal cord injury. Urol Int 12:270280. Utida C, Truzzi JC, Bruschini H, Simonetti R, Cedenho AP, Srougi M, Ortiz V (2005) Male infertility in spinal cord trauma. Int Braz J Urol 31:375383. van Arsdalen KN, Klein FA, Hackler RH, Brady SM (1981) Penile implants in spinal cord injury patients for maintaining external appliances. J Urol 126:331332. Vicino M, Loverro G, Simonetti S, Mei L, Selvaggi L (1999) The correlation between idiopathic leukocytospermia, embryo quality and outcome in the FIVET and ICSI procedures. Minerva Ginecol 51:413420.
Virag R (1982) Intracavernous injection of papaverine for erectile failure. Lancet 2:938. Wang E, Pfeffer LM, Tamm I (1981) Interferon increases the abundance of submembranous microlaments in HeLa-S3 cells in suspension culture. Proc Natl Acad Sci USA 78:6281 6285. Wang YH, Huang TS, Lien IN (1992) Hormone changes in men with spinal cord injuries. Am J Phys Med Rehabil 71:328332. Wang YH, Huang TS, Lin MC, Yeh CS, Lien IN (1993) Scrotal temperature in spinal cord injury. Am J Phys Med Rehabil 72:69. Wang S, Wang G, Barton BE, Murphy TF, Huang HF (2007) Benecial effects of vitamin E in sperm functions in the rat after spinal cord injury. J Androl 28:334341. Warner H, Martin DE, Perkash I, Speck V, Nathan B (1986) Electrostimulation of erection and ejaculation and collection of semen in spinal cord injured humans. J Rehabil Res Dev 23:2131. White RJ, Likavec MJ (1999) Spinal shock spinal man. J Trauma 46:979980. Wieder JA, Lynne CM, Ferrell SM, Aballa TC, Brackett NL (1999) Brown-colored semen in men with spinal cord injury. J Androl 20:594600. Wieder JA, Brackett NL, Lynne CM, Green JT, Aballa TC (2000) Anesthetic block of the dorsal penile nerve inhibits vibratory-induced ejaculation in men with spinal cord injuries. Urology 55:915917. Witt MA, Grantmyre JE, Lomas M, Richard J, Lipshultz LI (1992) The effect of semen quality of the electrical current and heat generated during rectal probe electroejaculation. J Urol 147:747749. Wolff H, Politch JA, Martinez A, Haimovici F, Hill JA, Anderson DJ (1990) Leukocytospermia is associated with poor semen quality. Fertil Steril 53:528536. Yang CC, Bradley WE (1999) Somatic innervation of the human bulbocavernosus muscle. Clin Neurophysiol 110:412 418. Yeoman RR, Sonksen J, Gibson SV, Rizk BM, Abee CR (1998) Penile vibratory stimulation yields increased spermatozoa and accessory gland production compared with rectal electroejaculation in a neurologically intact primate (Saimiri boliviensis). Hum Reprod 13:25272531. Zaslau S, Nicolis C, Galea G, Britanico J, Vapnek JM (1999) A simplied pharmacologic erection program for patients with spinal cord injury. J Spinal Cord Med 22:303307. Zasler ND, Katz PG (1989) Synergist erection system in the management of impotence secondary to spinal cord injury. Arch Phys Med Rehabil 70:712716. Zhu J, Brackett NL, Aballa TC, Lynne CM, Witt MA, Kort HI, Roudebush WE (2006) High seminal platelet-activating factor acetylhydrolase activity in men with spinal cord injury. J Androl 27:429433.
165

2009 Funcion Erectil en El Lesionado Medular

Cargado por

Información del documento

Descripción original:

Derechos de autor

Formatos disponibles

Compartir este documento

Compartir o incrustar documentos

Opciones para compartir

¿Le pareció útil este documento?

¿Este contenido es inapropiado?

Copyright:

Formatos disponibles

2009 Funcion Erectil en El Lesionado Medular

Cargado por

Copyright:

Formatos disponibles

REVIEW ARTICLE

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Prostatic massage Penile vibratory stimulation

Level of SCI T11 or below Level of SCI T10 or above

2010 Blackwell Verlag GmbH

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

Andrologia 42, 139165

Spinal cord injury

2010 Blackwell Verlag GmbH

Andrologia 42, 139165

Spinal cord injury

2010 Blackwell Verlag GmbH

Andrologia 42, 139165

Spinal cord injury

2010 Blackwell Verlag GmbH

Andrologia 42, 139165

Spinal cord injury

2010 Blackwell Verlag GmbH

Andrologia 42, 139165

Spinal cord injury

2010 Blackwell Verlag GmbH

Andrologia 42, 139165

Spinal cord injury

2010 Blackwell Verlag GmbH

Andrologia 42, 139165

Spinal cord injury

2010 Blackwell Verlag GmbH

Andrologia 42, 139165

Spinal cord injury

2010 Blackwell Verlag GmbH

Andrologia 42, 139165