Objectives: No investigation in mainland China concerning erectile function in men with liver transplant for benign end-stage liver disease has been performed.
Materials and Methods: Sixty men with a liver transplant for benign end-stage liver disease (post-liver transplant group) between October 2003 and December 2008 were invited to evaluate erectile dysfunction with the Chinese version of the 5-item international index of erectile function.Fifty-seven patients with benign end-stage liver disease (pre-liver transplant group) on the waiting list also were investigated.

Results: The proportion of sexually active patients in the post-liver transplant group was higher than it was in the pre-liver transplant group (80% [48/60] vs 47.7% [21/44]; P < .01). The mean International Index of Erectile Function-5 score of responders was significantly higher in the post-liver transplant group than it was in the pre-liver transplant group (15.9 ± 8.5 vs 8.5 ± 9.1; P < .01). The incidences of no erectile dysfunction, mild, mild-moderate, moderate, and severe erectile dysfunction and total erectile dysfunction were 15.9% (7/44), 9.1% (4/44), 15.9% (7/44), 0% (0/44), 59.1% (26/44), and 84.1% (37/44) in the pre-liver transplant group, and 33.3% (20/60), 20% (12/60), 25% (15/60), 0 (0/60), 21.7% (13/60), and 66.7% (40/60) in the post-liver transplant group. The pre-liver transplant group had higher incidence of severe erectile dysfunction and total erectile dysfunction and a lower incidence of no erectile dysfunction than did the post-liver transplant group (P < .05). There was a comparable incidence of mild and mild-moderate erectile dysfunction with the post-liver transplant group (P > .05). Variables associated with International Index of Erectile Function-5 score of the post-liver transplant patients included age, profession, and immunosuppressive protocol.
Conclusions: Liver transplant may improve erectile function in persons with benign end-stage liver disease, but erectile dysfunction remains a problem in the post-liver transplant patients.

Key words : Benign end-stage liver disease, Liver transplant, Erectile dysfunction

Introduction

Sexual dysfunction is characterized by a disturbance in sexual desire, psychophysiologic changes, and sexual response in men and women. It is prevalent in both sexes (ranging from 25% to 60% in women and 10% to 50% in men) and has been shown to be associated with increasing age and educational attainment.¹ In chronic liver disease, sexual dysfunction is due mainly to the physiological abnormality of the hypothalamic-pituitary-gonadal axis and the origin of liver disease.^2-4

Erectile dysfunction (ED), defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance,⁵ is a main domain of male sexual dysfunction^{.6, 7} Erectile dysfunction has been reported in nearly 13% of men, and the prevalence increased with age, from 2% in men 18 to 39 years old to 48% in those 70 years old.⁸ Patients with end-stage liver disease usually have some hypogonadism, with gynecomastia, testicular atrophy, alteration of hair distribution, reduction of libido, and hormonal disturbances, with reduced basal secretion of gonadotrophins, reduction of free and total testosterone, hyperprolactinemia, and hyperestrogenemia. All the above alterations may contribute to the development of ED.⁶

Liver transplant (LT) has become a widely accepted treatment for patients with end-stage liver disease. Theoretically, LT may lead to normalization of pathophysiologic abnormalities leading to resolution of ED. But sexual problems after LT may have been taboo, and health care professionals may not feel comfortable dealing with the questions regarding sexual health.² Therefore, research concerning sexual health after LT is limited. Most correlative studies have used small samples and nonvalidated methods with short-term follow-ups. The results of previous studies are controversial (Table 1).3,7,9 -12 So far, no specific study of this subject has been found with Chinese men as the subject population. This single-center study in China attempts to investigate ED of the patients with benign end-stage liver disease (BELD) before and after LT.

Materials and Methods

Patients

Patients followed for more than 3 months after LT for BELD between October 2003 and December 2008 at the Third Affiliated Hospital of Sun Yat-Sen University were selected by convenience sampling for inclusion in this study (post-LT group). Patients lost to follow-up were excluded. Patients with BELD on the waiting list of LT (pre-LT group) between October 2005 and December 2006 also were investigated. Patients were eligible for this study if they were married and were between 18 and 60 years of age. The study was approved by the Institutional Ethics Review Board Committee of the Third Affiliated Hospital of Sun Yat-Sen University. All protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration, and written, informed consent was obtained from all patients.

Survey

Subjects in post-LT group received an anonymous survey consisting of the Chinese version of the 5-item international index of erectile function (IIEF-5) at the out-patient clinic at least 3 months after undergoing an LT. Subjects in pre-LT group received the same survey in the in-patient or out-patient department once they were registered for an LT. The Chinese version of the IIEF-5 is a self-rating questionnaire.¹³ Patients who could not express their sexuality precisely were interviewed by a special investigator. For subjects lacking the opportunity for sexual activity in pre-LT group, the status of their sexual activities before hospitalization were used. All subjects in both groups were tested just 1 time.

Subjects in post-LT group also were asked to report the time that their libido recovered and sexual intercourse began since having their LT. A letter introducing and describing the questionnaire was given to the patients, which included an informed consent form explaining the aim of the study, the confidential nature of the data, the voluntary nature of participation, the ability to withdraw or not to participate without penalty, the use of data for research purposes only, and the guarantee that the study would not have any effect on the patient’s usual medical care. The name, phone number, and
e-mail address of a research contact person were provided.

Relevant clinical data were collected retrospectively from a review of case records. These included demographic details, education, profession, clinical indications for the LT, score on the model for end-stage liver disease (MELD) before the LT, time since the LT, immunosuppressive protocol, and liver function, nephrotoxicity, diabetes, cardiovascular disease, use of diuretics, use of glucocorticoids, and use of tobacco.

Abnormal liver function was defined as documented evidence of raised or rising serum glutamic-pyruvic transaminase and bilirubin as a result of post-LT complications that included biliary complications, vascular complications, graft rejection, and recurrent liver disease. Although the clinical presentation of these could vary greatly, all of the above were combined together as a single group for the purpose of statistical analyses. Nephrotoxicity was defined as documented evidence of raised or rising serum creatinine and urea nitrogen, together with treatment (for post-LT patients, including reduction of calcineurin inhibitors [CNIs] or conversion to an alternative agent) for nephrotoxicity. Diabetes was defined as documented evidence of raised or rising blood sugar. Cardiovascular disease was defined as documented evidence of hypertension, coronary disease, and arrhythmia.

Measures

Erectile dysfunction was assessed using the Chinese version of the IIEF-5, consisting of 4 items on erectile function, and 1 item on intercourse satisfaction. Item responses were scored on a 6-point scale. International index of erectile function-5 scores were obtained by calculating the sum of the item responses, with 1 being the worst possible score and 25 being the best.¹³ Rosen and associates¹⁴ suggested classes for evaluating the severity of ED: a score of 5 to 7 was defined as severe ED, 8 to 11 was defined as moderate ED, 12 to 16 was defined as mild-to-moderate ED, 17 to 21 was defined as mild ED, and a score above 22 was defined as no ED. For the Chinese version of IIEF-5, a score below 7 was defined as severe ED.¹³ The IIEF-5 has become a widely used self-rating scale for screening and diagnosing ED and severity of ED in clinical practice and research.

An exploratory univariate analysis was initially used to assess the possible effect of various clinical factors on IIEF-5 score for post-LT patients. The factors tested were age, education, profession, clinical indications for LT, pre-LT MELD score, time since LT, immunosuppressive protocol, and liver function (normal or abnormal), nephrotoxicity, diabetes, cardiovascular disease, use of diuretics, use of glucocorticoids, and use of tobacco. Based on findings from the initial univariate analysis, a principal component analysis was undertaken using a multiple linear regression analysis.

Statistical analyses

Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, New York, USA). Descriptive statistics were performed for all variables with a normality test for all quantitative variables. Intergroup comparisons were performed using the chi-square (or Fisher exact) test for qualitative variables, and the Mann-Whitney U test for quantitative variables. A P value < .05 was used to determine statistical significance. Associations between IIEF-5 score of the post-LT patients and the studied variables were sought with the multiple linear regression analysis. A P value < .05 was used to determine statistical significance.

Results

Of the 138 LT patients eligible for this study at our center, 60 were selected by convenience sampling for the post-LT group. An overall response of 100% (60/60) was achieved. The comparison of the demographics and some clinic features between selected patients and nonselected patients are shown in Table 2. There were no statistically significant differences between the selected and nonselected patients in terms of the parameters studied except for the immunosuppressive protocol and anti-hepatitis B virus (HBV) protocol. Fifty-seven patients were eligible for the pre-LT group and were invited to participate in the survey. An overall response rate of 77.2% (44/57) was achieved. The response rate of the pre-LT group was lower than that in the post-LT group (P < .01). Table 3 summarizes the demographics and some clinic features of the patients in the pre-LT and
post-LT groups. They were not significantly different (P > .05) between the groups except use of glucocorticoids.

Sexual activity and international index of erectile function-5 scores

Table 4 summarizes the proportion of sexually active patients and IIEE-5 scores in the pre-LT and post-LT group. At the time the survey was given, the proportion of sexually active patients among responders was higher in the post-LT group than it was in the pre-LT group (80% [48/60] vs 47.7% [21/44]; P < .01). As the IIEF-5 scores of responders in 2 groups did not follow a normal distribution, nonparametric tests were used. The IIEF-5 score was significantly higher for responders in the post-LT group than it was for responders in the pre-LT group (15.9 ± 8.5 vs 8.5 ± 9.1; P < .01). The IIEF-5 scores were higher for the sexually active patients in post-LT group than they were for persons in the pre-LT group; however, this did not reach statistical significance (19.6 ± 4.5 vs 16.7 ± 6.3; P =.066). For responders in the post-LT group, the medium time of libido recovering since having an LT was 60 days (7 to 365 d), and the medium time of sexual intercourse recovering since having an LT was 90 days (15 to 390 d).

Table 5 shows the incidence of ED among responders in both groups. The incidence of no ED, mild, mild-moderate, moderate, severe ED, and total ED were 15.9% (7/44), 9.1% (4/44), 15.9% (7/44), 0% (0/44), 59.1% (26/44), and 84.1% (37/44) for the pre-LT group, and 33.3% (20/60), 20% (12/60), 25% (15/60), 0 (0/60), 21.7% (13/60), and 66.7% (40/60) for the post-LT group. The pre-LT group had a higher incidence of severe ED and total ED and a lower incidence of no ED than did the post-LT group (P < .05). The pre-LT group had a comparable incidence of mild and mild-moderate ED with the post-LT group (P > .05).

Factors associated with international index of erectile function-5 score of the post-liver transplant group

The exploratory univariate analysis revealed that diagnosis, immunosuppressive protocol, cardiovascular disease, profession, and age might affect the IIEF-5 score of the post-LT patients (P < .01 or P < .05) (data not show). A principal component analysis then was undertaken with a multiple linear regression analysis. In the model of multiple linear regression analysis, profession 1 (government official, company staff, teacher, and doctor) were set up as a control subvariable for the variable of profession. Table 6 shows the factors associated with IIEF-5 scores of subjects in the post-LT group. The whole regression equation was statistically significant by an analysis of variations (P < .01). Variables associated with the IIEF-5 score of the post-LT group included profession, age, and immunosuppressive protocol. Compared with patients of profession 1, patients of profession 3 (businessman and private entrepreneur) had higher IIEF-5 scores (P < .05), while patients of profession 2 (farmer and labor) had comparable IIEF-5 scores (P > .05). Compared with patients using a tacrolimus-based immunosuppressive protocol, patients using a cyclosporine-based immunosuppressive protocol had higher IIEF-5 scores (P < .05). Age was negatively correlated with the IIEF-5 scores (P < .01)

Discussion

Several studies have found that male patients with end-stage liver disease who were or were not candidates for an LT were characterized by a high frequency of sexual inactivity and a high prevalence of ED. Their sexual dysfunction is due mainly to the abnormality of the physiology of the hypothalamic-pituitary-gonadal axis and the origin of liver disease.^2-4 For the pre-LT patients, depression and the psychological stress of awaiting an LT combined with a high consumption of drugs, diuretics, beta-blockers (for portal hypertension), and antidepressants appeared to favor sexual dysfunction.²

A study by Huyghe and associates⁶ found that 28.6% of patients (28/98) were sexually inactive, and 74% of the sexually active patients (52/70) had ED. A study by Sorrell and associates² found that 32.4% of candidates for an LT with end-stage liver disease reported sexual inactivity, 34.3% of sexually active candidates declared complete ED, and 20.6% declared partial ED. Toda and associates¹⁵ found a high total incidence of ED of 85% of patients with chronic liver disease, increasing as the Child-Pugh score worsened. Wang and associates¹⁶ found the 57% of patients with alcohol-related cirrhosis and 59% of patients with HBV-related cirrhosis had ED. On the contrary, a recent cross-sectional study in 93 male LT recipients showed a relatively low sexual dysfunction rate of 24% before LT.¹⁷

Our study demonstrated that men with BELD on a waiting list for an LT had a similar high prevalence of ED: 77.2% of patients responded to the survey, and only 47.7% of responders were sexually active; the IIEF-5 scores of the responders and sexually active patients were relatively low. Moreover, 84.1% of the responders had ED of different severities. The response rate was higher than those reported in previous studies by Ho and associates (42%)¹⁷ and Hart and associates (39%).¹⁸

The ability of the hypothalamic-pituitary-gonadal axis and sex steroid metabolism to resume physiological function after an LT has been demonstrated,⁴ although it has been suggested that some transplant recipients may have persisting abnormalities, especially among those transplanted for alcohol-related cirrhosis.⁵ However, the expectations that sexual functioning would recover after an LT have been misconstrued in several studies.1 Male sexual dysfunction often continues for partially unknown reasons, but it is favored by advancing age, post-LT depression, and prior irreversible toxic-metabolic damage. Immunosuppressants such as steroids, azathioprine, cyclosporine, tacrolimus, and sirolimus also can affect the hypothalamic-pituitary-gonadal axis by inhibiting androgenic synthesis.^11,19,20 However, it is unclear whether sexual dysfunction relates to treatment with CNIs alone, or with the whole set of pharmacological therapies administered after an LT.²¹ Sorrell and associates³ reported that among men with ED before an LT, ED remained unchanged after an LT in 34.6%. In the study by Ho and associates,¹⁷ twenty-four percent of responders reportedly had sexual dysfunction before LT, and this persisted in 15% after an LT. Moreover, 32% of the responders had a de novo sexual dysfunction after an LT, 23% had decreased libido, and 33% had difficulty in reaching orgasm with intercourse. In a recent study by Park and associates,⁹ two-thirds of the men were sexually active even if they had mild-to-moderate ED after an LT. The above results were confirmed in a recent study in which the proportion of men with ED remained unchanged despite improvement in sexual activity after an LT.¹¹

Our study demonstrates that persons in the post-LT group had a higher overall IIEF-5 score, a higher proportion of sexually active patients, and a lower incidence of ED than did persons in the pre-LT group. This suggests that LT may improve the erectile function of patients with BELD. However, the relative high incidence of ED (66.7%) in the post-LT group also suggests that ED remains a problem for the majority of post-LT patients.

Risk factors for ED in post-LT patients remain unknown mostly because these patients frequently have chronic clinical conditions (eg, diabetes, hypertension, and cardiovascular disease), which are identified as risk factors for ED in community-based studies. Several studies suggest that ED is influenced by multiple factors. Huyghe and associates¹¹ argued that the absence of sexual activity is associated with pretransplant sexual inactivity, age, cardiovascular disease, use of diuretics, anticoagulants, statins, and diabetes treatment. And the persistence of ED after an LT is associated with cardiovascular disease, diabetes, alcohol abuse, and use of antidepressants and angiotensin II receptor blockers. Burra and associates² revealed that the depression after an LT was the main risk factor for sexual dysfunction in men and women.

Our study shows that the erectile function after an LT might be affected by age, profession, and immunosuppressive protocol. In this study, businessmen and private entrepreneurs had higher IIEF-5 scores than did patients in other professions. Businessmen and entrepreneurs usually have a good deal of money and thus, need not worry about medical bills. Patients using a cyclosporine-based immunosuppressive protocol had higher IIEF-5 scores than did patients using tacrolimus-based immunosuppressive protocol. No significant difference in sexual function has ever been reported between patients treated with cyclosporine and those treated with tacrolimus.²² The mechanism of the phenomenon in our study remains unknown and requires further investigation.

This study is limited by its small size, retrospective nature, and nonlongitudinal assessment strategy. It also had a short interval from the LT to the survey and was based on data from a single center. The sample size of the pre-LT and post-LT groups in this study might not have been large enough. Therefore, future studies of ED in post-LT male patients should be based on multiple centers, and be prospective, randomized, controlled, and longitudinal trials. More medical variables (eg, quality of the transplanted graft) should be incorporated in future studies. More attention should be given to achieve maximum erectile function in men.

In conclusion, BELD patients are candidates for an LT and are a group characterized by a higher frequency of sexual inactivity, lower IIEF-5 scores, and a higher incidence of ED. Liver transplant may improve the erectile function of patients with BELD; however, ED still remains a problem in most LT patients. Erectile function after an LT might be affected by age, profession, and immunosuppressive protocol. Specific management of sexual problems should be addressed to improve the sex function of LT patients.

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