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- Review -
Sexual and reproductive function in end-stage renal disease
and effect of kidney transplantation
Mahboob Lessan-Pezeshki1, Shirin Ghazizadeh2
1Nephrology, Dialysis and Transplantation Department and
2Obstetrics and Gynecology Department, Tehran University of
Medical Sciences, Tehran 14197, Iran
Abstract
Advanced chronic kidney disease is associated with impaired spermatogenesis and testicular damage. Semen
analysis typically shows a decreased volume of ejaculate, oligo- or complete azoospermia, and a low percentage of
motile sperm. Erectile dysfunction (ED) is also common in patients with chronic renal failure (CRF) and is observed
in excess of 50% of these patients. There have been ongoing improvements in survival and quality of life after renal
transplantation. One of the most impressive aspects of successful renal transplantation in the young people is the
ability of the male patient to father a child. In this article we first review pathophysiology of reproductive failure in
end-stage renal disease (ESRD), then ED in ESRD and its management are discussed, finally sexual function in renal
transplant patients and management of ED in these patients are reviewed.
(Asian J Androl 2008 May; 10: 441_446)
Keywords: end-stage renal disease; erectile dysfunction; reproduction; kidney transplantation
Correspondence to: Prof. Mahboob Lessan-Pezeshki, Nephrology-Internal Medicine, Nephrology Department, Imam Khomeini Hospital,
Tehran University of Medical Sciences, Keshavarz Blvd, Tehran 14197, Iran.
Tel: +98-21-4087-643 Fax: +98-21-6937-321
E-mail: lessanpezeshki@yahoo.com
Received 2007-05-18 Accepted 2007-07-26
DOI: 10.1111/j.1745-7262.2008.00348.x
1 Introduction
For many male patients with renal failure, impotence and loss of libido and infertility are frequent occurrences.
These problems might improve but rarely normalize with the institution of maintenance dialysis, commonly resulting
in a decreased quality of life [1_3]. By comparison, a well-functioning renal transplant is much more likely to restore
sexual activity; however, some features of reproductive function might remain impaired.
The uremic milieu plays an important role in the genesis of sexual dysfunction in end-stage renal disease (ESRD).
Psychologic and physical stresses that might contribute to disturbances in sexual function are also commonly present
in patients with chronic renal failure [3, 4]. In the present article we first review pathophysiology of reproductive
failure in ESRD, then erectile dysfunction (ED) in ESRD and its management are discussed. Finally, sexual function
in renal transplant patients and management of ED in these patients are reviewed.
2 Pathophysiology of reproductive failure in ESRD
Advanced chronic kidney disease is associated with impaired spermatogenesis and testicular damage [3_5].
Semen analysis typically shows a decreased volume of ejaculate, oligoazoospermia 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.
The factors responsible for testicular damage in
uremia are not well understood. It is possible that
plasticizers in dialysis tubing, such as phthalate, might 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
[5]. The serum concentration of luteinizing hormone
(LH) is elevated in uremic men; this is a result of
diminished testosterone feedback.
Follicle stimulating hormone (FSH) secretion is also
elevated, although to a more variable degree [3].
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 indicate a poor
prognosis for recovery of spermatogenic function after
renal transplantation [3]. The basal levels of serum
prolactin are elevated in the majority of uremic patients, and
the response to thyrotropin-releasing hormone is reduced
and delayed [6]. The mechanisms for the hyperprolactinemia in chronic renal failure are not well defined.
An increased autonomous production rate of prolactin is
a major mechanism for the hyperprolactinemia but a
decreased metabolic clearance rate might also play a role.
3 ED in ESRD
ED is defined as the inability to achieve and maintain
an erection sufficient to permit satisfactory sexual
intercourse [7]. ED might result from psychological,
neurologic, hormonal, arterial or cavernosal impairment
or the combination of these factors. ED is observed in
more than 50% of patients with chronic renal failure
(CRF) [8]. Several factors appear to participate in the
genesis of impotence in CRF patients. These include
abnormalities in the neurohormonal control system of
the hypothalamic-pituitary-gonadal axis, secondary
hyperparathyroidism and dysfunction of the corporal
smooth muscle of the penis, or in the penis's response
to relaxing stimuli and/or derangements in the arterial
supply or the venous drainage of the penis [9].
Patients with a history of normal erectile function
prior to onset of renal disease might have a secondary
cause, such as 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, might
cause ED.
For patients without obvious causes of impotence
after an initial evaluation, consideration should be given
to psychological difficulties, such as stress or depression.
The occurrence of nocturnal penile tumescence (NPT)
among a large population of uremic patients is
significantly lower than that in the normal population [10]. The
administration of a nocturnal penile tumescence test might
help to distinguish between an organic and a
psychological disorder; the absence of an erection during sleep
suggests underlying organic dysfunction. A positive test,
however, does not exclude a physical cause [10].
4 Management of ED in ESRD
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
between 33% and 36% might enhance sexual function
[11]. The treatment of CRF patients with erythropoietin is
associated with a decreased in serum prolactin levels and
improvement in sexual dysfunction [12]. Correction of
hyperprolactinemia by bromocriptin is also associated
with an improvement in 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 [13].
Sildenafil has been effectively used in the treatment
of ED in both hemodialysis and peritoneal dialysis
patients and is often used for psychologic, vascular, or
neurogenic causes [14_17]. Sildenafil is a selective
inhibitor of phosphodiesterase type 5 (PDE5), which
inactivates cyclic guanosine monophosphate (GMP). Since
its release in March 1998, it has become the drug of
choice for most men with ED. When sexual stimulation
releases nitric oxide (NO) into the penile smooth muscle,
inhibition of PDE5 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 NO and
cyclic GMP are low [18]. Sildenafil has little effect on
libido. Among more than 3 700 men with average 6 months of exposure to sildenafil, most adverse events
were mild to moderate and self-limited in duration [19].
Among men taking 25_100 mg of sildenafil, 16% reported headache, 10% flushing, 7% dyspepsia, 4% nasal
congestion and 3% 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 [20]. 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 might be warranted before
sildenafil treatment is initiated. Adverse cardiovascular
events (nasal congestion, headache and flushing) are mild
and transient in the majority of men. The rate of serious
cardiovascular events (angina and coronary-artery disorder) is low. Sildenafil is absorbed well during fasting,
and the plasma concentrations are maximal within
30_120 min (mean, 60 min). It is eliminated predominantly
by hepatic metabolism, and the terminal half-life is
approximately 4 h. The recommended starting dose is 50
mg taken 1 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 [18]. Concurrent use
of sildenafil and nitrates in any form, regularly or
intermittently, is contraindicated. The administration of
testosterone to uremic men usually fails to restore libido or potency,
despite normalized serum testosterone.
A vacuum tumescence device might 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.
5 Reproductive function in renal transplant
patients
Kidney transplantation is the best and most effective
option that can be offered to patients with severe renal
damage to restore their health and to offer possibility of
recovering their sexual and reproductive functions.
Fertility as assessed by sperm count improves in half
of transplant patients. The sex hormone profile tends to
normalize [21].
The factors that might cause certain difficulties for
the recovery of sexual and reproductive functions in this
type of patient include prolonged use of peritoneal dialysis,
high FSH serum levels before the transplant, and a deficient
function of the graft [22].
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 [22].
Generally, immunosuppressive drugs commonly used
in patients with kidney transplants have not been
associated with adverse effects on patient spermatogenesis or
with teratogenic effects on their offspring [23].
Nevertheless, several studies conducted to evaluate the effects of
immunosuppressive regimens suggest that some of these
agents are potentially gonadotoxic because they affect
testicular function and decrease fertility. Cyclosporine
(CSA) is an important therapeutic agent and a common
component in multiple immunosuppressive regimens used
in recipients of kidney transplants [23, 24]. Some studies
imply that CSA is a potentially gonadotoxic drug: it has
produced adverse effects on reproductive capability in
experimental models as well as in humans. In certain
animal species, such as the Sprague-Dawley strain rats,
Seethalakshmi et al. [25] 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. It has also been possible to
observe the adverse effect of CSA by means of
testicular biopsies performed in dogs [26] and rats [27] treated
with CSA for short periods, where marked abnormalities
in spermatogenesis have been seen. CSA might impair
testosterone biosynthesis through direct damage to leydig
cells and germinal cells, and a direct impairment of the
hypothalamic-pituitary-gonadal axis has been suggested.
Computer-aided sperm analysis 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 by leveling
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 [28].
Azathioprine (AZA), another drug that is frequently
combined with CSA, is considered to be genotoxic [29].
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 [29].
Kaczmarek et al. [30] found that heart transplant
recipients treated with sirolimus had significantly lower
free testosterone levels and significant higher levels of
gonadotropic hormones, LH and FSH compared with a calcineurin inhibitor-based immunosuppression group.
There is no increased incidence of neonatal
malformations in pregnancies fathered by transplant
recipients [21]. However, there is some concern about infertility
associated with Ganciclovir, which is used for treatment of
cytomegalovirus infection in transplant patients [31].
6 Sexual function 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 might improve erectile function and
return libido, in many cases some degree of sexual
dysfunction might persist.
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, including effects on libido and
erection [32]. Medications are implicated in ED include
beta blockers (propranolol and labetalol), alpha blockers
(prazosin), sympatholytics (clonidine), vasodilators
(hydralazine) and diuretics (thiazides and
spironolactone).
Other drugs that might also play a role in ED in
transplant patients are: HMG-CoA reductase inhibitors
(lovastatin and simvastatin), antidepressants (serotonin
reuptake inhibitors, tricyclics and monoamine oxidase
inhibitors) and H2 antagonists (cimetidine, ranitidine and
famotidine).
Ketoconazole, which is used in some transplant
centers to increase cyclosporine levels and reduce the costs
of calcineurin inhibitors, can cause ED because of its
antiandrogenic action.
Additional factors such as smoking and alcohol
intake might account for failure of male sexual function to
improve after transplantation.
Cigarette smoking might induce vasoconstriction and
penile venous leakage because of its contractile effect on
the cavernous smooth muscle [33]. 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 ED. Chronic alcoholism might
cause hypogonadism and polyneuropathy, which can affect penile nerve function [34].
Autonomic neuropathy can impair erectile function,
and interruption of both hypogastric arteries can
occasionally impair vascular supply.
7 Management of ED in renal 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 ED is not associated with
hypogonadism [18]. There is no specific contraindication to
use sildenafil in transplant patients so long as standard
precautions are taken regarding concomitant coronary
artery disease. Sexual activity was thought to be a likely
contributor to myocardial infarction in only 0.9% of 858
men in one study [35]. Therefore, the absolute increase
in risk caused by sexual activity is low (1 chance in one
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 ED is
common is approximately 170 per one 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 USA.
Therefore, nitrate therapy is an absolute contraindication
to sildenafil therapy [18].
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, Wedgewood
Pharmacy, Swedesboro, NJ, USA). The usual dose of
trimix solution ranges from 0.1 mL to 0.5 mL. The rate of
response to this solution is as high as 90% [36].
The majority of men with functioning kidneys can
look forward to a return of sexual activity comparable to
pre-illness level. However, sexual impairment might
persist in some patients after transplantation, emphasizing
the need for further evaluation in this group of patients.
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