2.1. Physiology of reproduction in men
The male reproductive tract consists of the testis, epididymis, vas deference, prostate, seminal vesicles, ejaculatory duct, bulbouretral glands, and urethra. The testes contain two cell types: the Sertoli cells, which line the seminiferous tubules (the site of spermatogenesis), and the Leydig cells (the site of androgen synthesis). In the male, the pituitary gland secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which act on the testes. LH stimulates the synthesis and secretion of testosterone by the Leydig cells, and FSH stimulates the sertoli cells to secrete inhibin. FSH and testosterone act on the seminiferous tubules to stimulate spermatogenesis. In human it takes about 75 days for spermatogonia to develop into mature sperm cells (Berek 2002).
During ejaculation, mature spermatozoa are released from the vas deferens along with fluid from the prostate, seminal vesicle, and the bulbourethral glands. The semen released is a gelatinous mixture of spermatozoa and seminal plasma; however it thins out 20 -30 minutes after ejaculation by a process called liquefaction (Berek 2002).
Both LH and FSH play roles in normal spermatogenesis. Thus, spermatogenesis does not occur spontaneously in men who have hypogonadotropic hypogonadism of prepubertal onset. Spermatogenesis can be initiated in these men by the administration of human chorionic gonadotropin (hCG), which has potent LH effects, and an FSH preparation, such as human menopausal gonadotropin (hMG) ( Finkel 1985).
2.2. Male reproduction in end stage renal disease
For many male patients with renal failure, impotence and loss of libido have been seen frequently; these problems may improve but rarely normalize with the institution of maintenance dialysis, commonly resulting in a decreased quality of life ( Holdsworth 1978; Diemont 2000 ; Rosas 2003). By comparison, a well-functioning renal transplant is much more likely to restore sexual activity; however, some features of reproductive function may remain impaired.
The uremic milieu plays an important role in the genesis of sexual dysfunction in end stage renal disease. Psychologic and physical stresses that may contribute to disturbances in sexual function are also commonly present in patients with chronic renal failure ( Holdsworth 1978; Steele 1996; Toorians, Janssen et al. 1997).
2.2.1. Gonadal function
Advanced chronic kidney disease is associated with impaired spermatogenesis and testicular damage ( Holdsworth 1977; Holdsworth 1978). Semen analysis typically shows a decreased volume of ejaculate, oligo- or complete azoospermia, and a low percentage of motile sperm. Testicular histology shows reduced spermatogenic activity varying from decreased numbers of mature spermatocytes to complete aplasia of germinal elements. Other findings include damage to the seminiferous tubules, atrophy of Sertoli cells, and interstitial fibrosis and calcifications.
The factors responsible for testicular damage in uremia are not well understood. It is possible that plasticizers in dialysis tubing, such as phthalate, may play a role in patients undergoing maintenance hemodialysis.
Uremia also impairs gonadal steroidogenesis. The serum total and free testosterone concentrations are typically reduced, although the binding capacity and concentration of sex hormone-binding globulin are normal ( Lim 1976; Levitan 1984; de Vries 1984). Another manifestation of diminished testosterone secretory capacity is the subnormal and delayed testosterone response to the administration of human chorionic gonadotropin (HCG), a compound with luteinizing hormone-like actions (Stewart-Bentley 1974). By comparison, although the total plasma estrogen concentration is frequently elevated, the serum estradiol concentration is typically normal (Lim 1978).
2.2.2. Pituitary function
The serum concentration of luteinizing hormone (LH) is elevated in uremic men (Lim 1978); this is due to diminished testosterone feedback.
Follicle stimulating hormone (FSH) secretion is also elevated, although to a more variable degree ( Holdsworth 1978; de Vries 1984). Elevated FSH levels are probably the result of decreased testosterone and inhibin, a Sertoli cell product. The plasma FSH concentration tends to be highest in those uremic patients with the most severe damage to seminiferous tubules and presumably the lowest levels of inhibin. It has been suggested that increased FSH levels may portend a poor prognosis for recovery of spermatogenic function after renal transplantation. The gonadotropin reserve is generally intact, since the plasma level of both gonadotropins increased appropriately following administration of gonadotropin-releasing hormone (GnRH) (LeRoith 1980). The appropriate increase in FSH and LH in response to the administration of clomiphene (a nonsteroidal antiestrogen that stimulates gonadotropin secretion by blockade of estrogen mediated negative feedback on the hypothalamus) (Lim 1978), also indicates a normal gonadotropin reserve.
The basal levels of serum prolactin are elevated in the majority of uremic patients, and the response to thyrotropin-releasing hormone (TRH) is reduced and delayed (Hagen C 1976). The mechanisms for the hyperprolactinemia in chronic renal failure are not well defined. Increased autonomous production rate of prolactin is a major mechanism for the hyperprolactinemia but decreased metabolic clearance rate may also play a role (Cowden 1981). The demonstration of resistance to stimulation or suppression of prolactin in CRF is consistent with increased autonomous production (Pece 1979). The state of secondary hyperparathyroidism of CRF may contribute to the increased production rate of prolactin, because PTH stimulates prolactin secretion (Issac 1978). The treatment of CRF patients with erythropoietin was associated with a decreased in serum prolactin levels and improvement in sexual dysfunction (Schaefer, Stanhope et al. 1989), but did not normalize rate of the response to TRH (Ramirez 1976). These observations suggest that either anemia and/or deficiency of erythropoietin per se participate in the genesis of the hyperprolactinemia of CRF.
Variable degrees of gynecomastia are often encountered in the male uremic patient treated with maintenance hemodialysis (Lim 1978). Gynecomastia usually develops during initial months of dialysis and regresses as dialysis continues. It may be transient or may last for periods of several months. The etiology may be related to the improvement in the nutritional status of uremic patient with dialysis theray and, as such, is similar to the mechanism of refeeding gynecomastia. It must be emphasized that in almost all cases of Gynecomastia, there is an alteration either in the ratio between the serum level of androgen and estrogen, in favor of the latter, or in the ratio between the action of androgen and estrogen at the tissue level ( Sawin 1973). Indeed, in patients with advanced CRF and those treated with hemodialysis, the ratio between the serum levels of free testosterone and estradiol is reduced because of a decreased in testosterone levels.
2.3. Erectile dysfunction in end stage renal disease:
Erectile dysfunction is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse. It may result from psychologic, neurologic, hormonal, arterial or cavernosal impairment or from a combination of these factors. Most of the studies in sexual dysfunctions in CRF patients have focused on impotence. Erectile dysfunction is common in patients with CRF and is observed in excess of 50% of these patients (Procci 1981). These data are based on results obtained from interviews with or by the completion of questionnaires by the patients and/or their spouses. Several factors appear to participate in the genesis of impotence in CRF patients. These include abnormalities in the neurohormonal control system of erection hormones of the hypothalamic-pituitary-gonadal axis, secondary hyperparathyroidism and, dysfunction of the corporal smooth muscle of the penis or in their response to relaxing stimuli and/or derangements in the arterial supply or the venous drainage of the penis (Schrier RW 2001). Patients with a history of abnormal erectile function prior to the onset of renal disease may have a secondary cause, such as a neuropathy or peripheral vascular disease.
The presence of a neurogenic bladder suggests an underlying neuropathy, while findings of peripheral vascular disease point toward inadequate penile blood flow. The lack of secondary sexual characteristics combined with small soft testicles suggests hypogonadism. The ingestion of a number of medications, such as beta blockers and tricyclic antidepressants, may be a cause of erectile dysfunction.
Among those without an obvious cause of impotence after an initial evaluation, consideration should be given to a psychologic difficulty, such as stress or depression. The values of Nocturnal Penile Tumescence (NPT) among a large population of uremic patients are significantly lower than normal. The administration of a nocturnal penile tumescence test may help distinguish between an organic and a psychologic disorder; the absence of an erection during sleep suggests underlying organic dysfunction. A positive test, however, does not exclude a physical cause.
The first step in the treatment of uremic men with sexual dysfunction is increasing the delivered dose of dialysis, discontinuing medications with side effects of impotence and correcting the anemia of chronic renal disease. As an example, the administration of recombinant human erythropoietin to raise the hematocrit to 33 to 36 percent may enhance sexual function ( Delano 1989).
Sildenafil has been effectively used in the treatment of erectile dysfunction in both hemodialysis and peritoneal dialysis patients and is often used for psychologic, vascular, or neurogenic causes ( Ifudu 1998; Palmer 1999; Turk 2001; Seibel 2002; Rosas 2003; Grossman 2004). Concurrent use of sildenafil and nitrates in any form, regularly or intermittently, is contraindicated.
Since the elevation of serum levels of prolactin plays a role in the impotence of male uremic patient, correction of hyperprolactinemia by bromocriptin is also associated with improvement of sexual dysfunction.
Cabergoline, which causes nausea much less often than does bromocriptine and is at least as effective in treating hyperprolactinemia, should be tried first (Biller BM; Molitch ME; Vance ML; Cannistraro KB; Davis KR; Simons JA; Schoenfelder JR; Klibanski A 1996 ). The administration of testosterone to uremic men usually fails to restore libido or potency, despite normalized serum testosterone.
A vacuum tumescence device may be effective in restoring potency in uremic impotent males unresponsive to medical therapy. Administration of zinc is also a reasonable therapeutic option in uremic men.
2.4. Renal transplantation
Kidney transplantation is the best and most effective option that can be offered to patients with severe renal damage to restore their health and the possibility of recovering their sexual and reproductive functions.
After successful transplantation, about two thirds of male patients observe improved libido and a return of sexual function to predialysis levels. Fertility as assessed by sperm counts, improves in half patients. The sex hormone profile tends to normalize; plasma testosterone and follicle stimulating hormone levels increase; and luteinizing hormone levels which may be high in dialysis patients, decrease to normal or low levels (Danovitch GM 2005).
The factors that might cause certain difficulties for the recovery of sexual and reproductive functions in this type of patients include prolonged use of peritoneal dialysis, high follicle stimulating hormone (FSH) serum levels before the transplant, and a deficient function of the graft (De Celis and Pedron-Nuevo 1999).
A certain improvement has been reported as to semen quality in the three main parameters (number, morphology, and motility of the spermatozoa) in patients after kidney transplantation (De Celis and Pedron-Nuevo 1999).
Several studies conducted to evaluate the effects of immunosuppressive regimens suggest that some of these agents are potentially gonadotoxic since they affect testicular function and decrease fertility. This is mainly due to an indirect effect on the hypothalamus–pituitary–gonadal axis, or directly suppressant on the germinal epithelium of the testis, where the spermatogenetic process is primarily affected because of an interruption of the cycle needed for the development of an adequate amount of normal spermatozoa.
This would result in oligo/asthenozoospermia, teratozoospermia, or azoospermia. Cyclosporine (CSA) is an important therapeutic agent and a common component in multiple immunosuppressive regimens used in recipients of kidney transplants and for a growing number of autoimmune disorders. Some studies imply that CSA is a potentially gonadotoxic drug, producing adverse effects on the reproductive capability in experimental models as well as in humans. In certain animal species, such as the Sprague–Dawley strain rats, Seethalakshmi et al. showed that the administration of CSA induces a deficient intratesticular synthesis of androgens and a reduction in spermatogenesis, although this reduction was reversible after exogenous gonadotrophins were administered ( Seethalakshmi 1990 ). On the other hand, it has also been possible to observe the adverse effect of CSA by means of testicular biopsies performed in dogs (Seethalakshmi 1988) and rats (Seethalakshmi 1990) treated with CSA for short periods, where marked abnormalities in spermatogenesis were seen. Cyclosporine (CSA) may impair testosterone biosynthesis through direct damage to leydig cells and germinal cells, an indirect impairment of the hypothalamic-pituitary-gonadal axis has also been suggested.
Computer-aided sperm analysis (CASA) in infertile renal transplant recipients showed that both sperm concentration and straight line velocity (VSL) were inversely correlated to the cyclosporine whole blood trough levels. Stabilization of the cyclosporine whole blood trough level within the target therapeutic level could improve the fertility potential in kidney transplant recipients. Duration of hemodialysis before transplantation is also important in this regard. The time spent on hemodialysis is inversely correlated with the percentage of motile spermatozoa and the amplitude of lateral head displacement (ALH) (Eid, Abdel-Hamid et al. 1996).
Azathioprine (AZA), another drug that is frequently combined with CSA, is considered to be genotoxic (Olshan 1994). However, very few studies have analyzed the effects of AZA on the reproductive function of humans. Several studies suggest that prednisone might not be involved in sperm cell damage.
Kaczmarek and coworkers found that heart transplant recipients treated with sirolimus had significantly lower free testosterone levels and significant higher levels of gonadotropic hormones luteinizing hormone and follicle-stimulating hormone compared with calcineurin inhibitor-based immunosuppression group (Kaczmarek 2004). Patients treated with sirolimus throughout the post-transplant period have a significantly reduced total sperm count compared to patients who did not receive sirolimus and a decreased proportion of motile spermatozoa. Moreover, the fathered pregnancy rate was lower in patients receiving sirolimus-based regimens (Zuber, Anglicheau et al. 2008).
There is also concern about infertility associated with Ganciclovir which is used for treatment of cytomegalovirus (CMV) infection in transplant patients (Nevins and Dunn 1992). There is no increased incidence of neonatal malformations in pregnancies fathered by transplant recipients (Danovitch GM 2005).
2.4.1. Sexual functions in renal transplant patients
Renal transplant recipients have all suffered from uremia. They have frequently spent a significant amount of time on dialysis and often have other comorbidities including hypertension and diabetes. Although a successful transplant may improve erectile function and return of libido, in many cases some degree of sexual dysfunction may persist. On the contrary a recent study showed that, erectile function worsens after RT in patients<45 yr (Mirone, Longo et al. 2009).
Hypertension is common among transplant patients; CSA can exacerbate preexisting high blood pressure and also induce hypertension in patients, who had normal blood pressure prior to the kidney transplant.
Antihypertensive medications have negative effects on male sexual functions, such as libido and erection (Matthew RW 2005). Those medications which are implicated in erectile dysfunction include beta blockers (propranolol, labetalol), Alpha blockers (prazosin), sympatholytics (clonidine), vasodilators (hydralazine), and diuretics (thiazides, spironolactone).
Other drugs which may also play a role in erectile dysfunction in transplant patients are: HMG- CoA reductase inhibitors (lovastatin, simvastatin), antidepressant (serotonin reuptake inhibitors, tricyclics, monoamine oxidase inhibitors) and H2 antagonists (cimetidine, ranitidine, famotidine).
Ketoconazole which is used in some transplant centers in order to increase cyclosporine level and reducing the cost of calcineurin inhibitors can cause erectile dysfunction because of its antiandrogenic action.
Additional factors such as smoking and alcohol intake may account for failure of male sexual function to improve after transplantation.
Cigarette smoking may induce vasoconstriction and penile venous leakage because of its contractile effect on the cavernous smooth muscle (Juenemann 1987). Alcohol in small amounts improves erection and increases libido because of its vasodilatory effect and the suppression of anxiety; however, large amounts can cause central sedation, decreased libido, and transient erectile dysfunction. Chronic alcoholism may cause hypogonadism and polyneuropathy, which may affect penile nerve function (Miller 1988).
Autonomic neuropathy may impair erectile function, and interruption of both hypogastric arteries may occasionally impair vascular supply.
2.4.2. Management of erectile dysfunction in transplant patients
Male patients should be asked about their sexual function and referred for urologic evaluation when necessary. Historically, androgens were touted as enhancing male sexual function. Today, more effective treatments are available, and testosterone therapy should be discouraged in men in whom erectile dysfunction is not associated with hypogonadism (Lue T F 2000). Sildenafil is a selective inhibitor of phosphodiesterase type 5, which inactivates cyclic GMP. Since its release in March 1998, it has become the drug of choice for most men with erectile dysfunction. When sexual stimulation releases nitric oxide into the penile smooth muscle, inhibition of phosphodiesterase type 5 by sildenafil causes a marked elevation of cyclic GMP concentrations in the glans penis, corpus cavernosum, and corpus spongiosum, resulting in increased smooth-muscle relaxation and better erection. Sildenafil has no effect on the penis in the absence of sexual stimulation, when the concentrations of nitric oxide and cyclic GMP are low (Lue T F 2000). Sildenafil has little effect on libido. Among more than 3700 men with 1631 patient years of exposure to sildenafil, most adverse events were mild to moderate and self-limited in duration (Esteban de la Rosa, Bravo Soto et al. 2003). Among men taking 25 to 100 mg of sildenafil, 16 percent reported headache, 10 percent flushing, 7 percent dyspepsia, 4 percent nasal congestion, and 3 percent abnormal vision (described as a mild and transient color tinge or increased sensitivity to light). These rates were twice as high among men taking 100 mg of sildenafil as among men who were taking lower doses. The visual effect is probably related to inhibition of phosphodiesterase type 6 in the retina. No chronic visual impairment has been reported, and the incidence of visual side effects was similar in diabetic and nondiabetic men (Price 1998). Nevertheless, because of the short duration of the clinical trials and the difficulty in detecting subtle retinal changes, the long-term safety of sildenafil treatment is still unknown. In men with retinal diseases, an ophthalmologic consultation may be warranted before sildenafil treatment is initiated. Adverse cardiovascular events (nasal congestion, headache, and flushing) were mild and transient in the majority of men. The rate of serious cardiovascular events (angina and coronary-artery disorder) is low. Sexual activity was thought to be a likely contributor to myocardial infarction in only 0.9 percent of 858 men in one study (Muller, Munder et al. 2009). Thus, the absolute increase in risk caused by sexual activity is low (one chance in a million for a healthy man). According to data from the National Center for Health Statistics and the Framingham Heart Study, the rate of death from myocardial infarction or stroke for men in the age range in which erectile dysfunction is common is approximately 170 per million men per week. Therefore, it appears that sildenafil therapy is safe for most men. Nevertheless, given that most of the men who died had underlying cardiovascular disease; cardiovascular status should be carefully assessed before treatment. The combination of nitrates and sildenafil has resulted in severe hypotension and 16 deaths in the United States. Therefore, nitrate therapy is an absolute contraindication to sildenafil therapy (Lue T F 2000).
Sildenafil is absorbed well during fasting, and the plasma concentrations are maximal within 30 to 120 minutes (mean, 60). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about four hours. The recommended starting dose is 50 mg taken one hour before sexual activity. The maximal recommended frequency is once per day. On the basis of effectiveness and side effects, the dose may be increased to 100 mg or decreased to 25 mg (Lue T F 2000). There is no specific contraindication to use of sildenafil (Viagra) in transplant patients so long as standard precautions are taken regarding concomitant coronary artery disease.
Oral vardenafil (Phosphodiesterase-5 Enzyme Inhibitor) therapy has a high efficacy and a low incidence of adverse events for kidney transplant recipients with ED (Yang, Ju et al. 2008). Vardenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE-5 by vardenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. so it can prolong erectile duration of ED patients (Wang and Huang 2009); at recommended doses, it has no effect in the absence of sexual stimulation.
Transurethral administration of alprostadil (synthetic form of prostaglandin E1) or intracavernous injection resulting in an erection sufficient for intercourse has been used successfully. The most effective intracavernous therapy used is a three-drug mixture containing papaverine, phentolamine, and alprostadil (trimix). The usual dose of trimix solution ranges from 0.1 to 0.5 ml. The rate of response to this solution is as high as 90 percent (Bennett 1991). In case of drug treatment failure, penile prosthesis can be considered even in transplanted patients (Lasaponara, Pasquale et al. 2009; Phe, Roupret et al. 2009).