1. The goal of liver transplantation is not only to ensure the survival of patients but also to offer patients the opportunity to achieve a good balance between the functional efficacy of the graft and their psychological and physical integrity. The quality of life after transplantation may be affected by unsatisfactory sexual activity and reproductive performance.
2. Sexual dysfunction and sex hormone disturbances are widely reported in men and women with chronic liver disease before liver transplantation.
3. Successful liver transplantation should lead to improvements in sexual function and sex hormone disturbances in both men and women, therefore improving reproductive performance, but immunosuppressive drugs may interfere with hormone metabolism.
4. Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy, but fetal and maternal outcomes should be regularly assessed.
Sexual dysfunction is characterized by disturbances in sexual desire and in the psychophysiological changes associated with the sexual response cycle in men and women; it is highly prevalent in both sexes, being found in 10% to 50% of men and in 25% to 60% of women. Despite the potential impact of these disorders on quality of life, epidemiological data are relatively scant, and even less information has been reported on liver transplant recipients.
Considering the data available on the general population, an important survey related to sexual behavior in 1749 women and 1410 men 18 to 59 years old, was reported. The main outcome measure was the risk of experiencing sexual dysfunction and negative concomitant outcomes, and the authors reported that sexual dysfunction was more prevalent in women (43%) than in men (31%) and was associated with age and educational attainment.1
SEXUAL DYSFUNCTION IN MEN WITH LIVER DISEASE
Erectile dysfunction is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse, and it results from various causes (Table 1).2
Table 1. Classification and Common Causes of Erectile Dysfunction
Category of Erectile Dysfunction
NOTE: This table was adapted from the New England Journal of Medicine.2
Loss of libido, overinhibition, or impaired nitric oxide release
Stroke or Alzheimer's disease spinal cord injury
Failure to initiate nerve impulse or interrupted neural transmission
Radical pelvic surgery
Loss of libido and inadequate nitric oxide release
Inadequate arterial flow or impaired veno-occlusion
Antihypertensive and antidepressant drugs
Systemic diseases and aging
Usually multifactorial and resulting in neural and vascular dysfunction
Chronic renal failure
Coronary heart disease
Erectile dysfunction was 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. A history of chronic medical illness increased the risk of erectile dysfunction, which was higher for current smokers compared with never smokers and exsmokers.3 Another study on erectile disorder was performed in 75 male veterans with chronic medical illness. Patients whose partners participated in the evaluation were compared with those whose partners were not involved, and agreement on measures between patients and partners was examined. The analysis was performed to assess the primary dimensions underlying the variance in mental health and sexual functioning variables, and in this respect, 5 factors were identified, accounting for 65.5% of the variance. Anxiety and social isolation accounted for 25.4% of the variance.4
In patients with end-stage liver disease, hypogonadism and signs of feminization can be seen. Testicular atrophy, low testosterone levels, decreased libido, infertility, reduced secondary sex hair, and gynecomastia are found in men with cirrhosis. Fifty percent of patients with cirrhosis presents reduced spermatogenesis and peritubular fibrosis.5 These alterations are dependent on the severity of the liver disease and are more pronounced in patients with a higher Child-Pugh score.6, 7 It has been reported that patients with no sexual activity have the highest mean Model for End-Stage Liver Disease (MELD) scores,8 and similarly, the MELD score correlates with erectile dysfunction.9
Gynecomastia and impotence of patients with cirrhosis are augmented by the chronic use of spironolactone, a receptor antagonist of aldosterone and testosterone, which reduces testosterone levels and slightly increases the levels of estradiol. The clinical signs of hypogonadism are more pronounced in alcoholic patients because of the direct effect of ethanol on the testes. In primary hemochromatosis, excessive iron accumulation and toxicity in the testes cause hypogonadism with testicular atrophy, and patients may present with impotence or infertility, low testosterone, and azoospermia.10, 11
DHEAS, dehydroepiandrosterone sulfate; FDA, Food and Drug Administration; FSH, follicle-stimulating hormone; LH, luteinizing hormone; MELD, Model for End-Stage Liver Disease; SHBG, sexual hormone binding globulin; TSH, thyroid-stimulating hormone.
SEXUAL DYSFUNCTION IN WOMEN WITH LIVER DISEASE
Chronic anovulation is a common problem in women with systemic diseases and is displayed with secondary amenorrhea, oligomenorrhea, or irregular episodes of metrorrhagia. Amenorrhoea is common in women with alcoholic and nonalcoholic chronic liver disease, and testosterone, estradiol, prolactin, and luteinizing hormone (LH) may vary significantly in comparison with normal subjects. Amenorrhoea is not always related to the duration or severity of liver disease, and it may arise from hypothalamic-pituitary dysfunction occurring at any stage.12 Chronic alcohol abuse causes disturbances in the hormonal status and the reproductive performance of women.13
SEXUAL FUNCTION AFTER LIVER TRANSPLANTATION IN MEN AND WOMEN
Successful liver transplantation leads to improvements in sex hormone disturbances in both men and women, but immunosuppressive drugs may interfere with hormone metabolism. The proportion of sexually inactive men was reported to decrease from 29% (before transplantation) to 15% (after transplantation), but the proportion of men with erectile dysfunction remained unchanged. The absence of sexual activity was associated with pretransplant sexual inactivity, age, cardiovascular disease, use of diuretics, anticoagulants, statins, and treatment for diabetes. Cardiovascular disease, posttransplantation diabetes, alcohol abuse, antidepressants, and angiotensin II receptor blockers were associated with erectile dysfunction after liver transplantation.14
Women achieve normal menstrual function and fertility a few months after transplantation, and the recommendation to women of reproductive age who undergo liver transplantation is to observe the timing and pattern of menstruation, sexual activity, contraception, and the incidence of pregnancy and gynecological disorders. In the year before transplantation, 42% of women reported regular menstrual cycles, 28% reported irregular and unpredictable bleeding, and 30% reported amenorrhea, whereas after transplantation, 48% experienced regular menses, 26% experienced irregular bleeding, and 26% experienced amenorrhea.15
IMMUNOSUPPRESSIVE DRUGS AND GONADAL FUNCTION
Since 2004, several studies have emphasized the potential impact of sirolimus on male gonadal function.16–20 Kaczmarek et al.17 first reported a significant decrease in free testosterone and a significant increase in LH and follicle-stimulating hormone (FSH) levels in a series of 132 heart transplant patients treated with sirolimus. A recent and very comprehensive review21 of all published studies on transplant patients who received mammalian target of rapamycin inhibitors showed consistent evidence of sirolimus-related gonadal function suppression and increases in FSH and LH concentrations.
Data concerning the impact of sirolimus on erectile function and fertility are still lacking. In a recent cross-sectional study,19 despite lower total testosterone levels and higher FSH and LH levels, no significant difference in sexual scores was found between patients treated with sirolimus and a control group. However, laboratory studies on rats and primates22 seem to demonstrate a direct link between sirolimus and decreased spermatogenesis.
Female patients of reproductive age must be counseled about the possibility of pregnancy and the use of contraception, and pregnancy should be avoided for the first 6 to 12 months after transplantation, although some centers advocate waiting 24 months. Barrier contraception seems to be the safest option for these patients.
PREGNANCY AFTER LIVER TRANSPLANTATION
The first pregnancy after liver transplantation was reported in 1978 by Walcott and colleagues.23 National registries have been established to record pregnancies along with fetal and maternal outcomes in patients who have undergone organ transplantation. In 2006, the National Transplantation Pregnancy Registry (Philadelphia, PA) reported 202 pregnancy outcomes in 121 liver transplants recipients.24
Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy. Acute cellular rejection may occur in pregnant liver transplant recipients, but no difference is generally reported in comparison with nonpregnant recipients. The treatment is usually based on an increase in immunosuppression or on the use of intravenous boluses of steroids.
Liver transplant recipients with recurrent hepatitis C or hepatitis B nonetheless appear to be at risk of worse graft function in the event of pregnancy, and antiviral drugs are generally contraindicated in pregnancy because of their teratogenic effects.
The use of immunosuppressive drugs should be maintained during pregnancy because none of them has been found to be teratogenic, and drug concentrations should be carefully monitored.25
In our center, in women willing to be or already pregnant, we maintain, if possible, the patient with a single immunosuppressive drug regimen, such as cyclosporine or tacrolimus, maintaining standard levels of immunosuppression during pregnancy that are appropriate for the time course. We have had experience, however, of pregnancies in patients on azathioprine with no detrimental effect on birth.
Immunosuppressive Drugs and Pregnancy
The US Food and Drug Administration (FDA) categorizes the safety of drugs in pregnancy on the basis of available evidence (Table 2).
Table 2. US Food and Drug Administration Categories of Safety for Drugs in Pregnancy
Controlled studies show no risk: adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus.
No evidence of risk in humans: either animal findings show risk (but human findings do not) or, if no adequate human studies have been performed, animal findings are negative.
Risk cannot be ruled out: human studies are lacking and animal studies are either positive for fetal risk or lacking as well. However, potential benefits may justify the potential risk.
Positive evidence of risk: investigational or postmarketing data show risk to the fetus. Nevertheless, potential benefits may outweigh the risk.
Contraindicated in pregnancy: studies in animals or humans or investigational or postmarketing reports have shown fetal risk that outweighs any possible benefit to the patient.
Although controversy surrounds the transplacental transfer of cyclosporine, its teratogenic potential appears to be low. Premature labor and low birth weight have been reported, but major malformations have been seen in 4.1% of live births; this rate is not significantly higher than that noted in the general population.26 Cyclosporine is considered a class C drug in terms of its risk for pregnancy by the FDA.
The neonatal malformation rate in patients on tacrolimus is similar to the rate associated with cyclosporine.26 Tacrolimus is considered a class C drug in terms of its risk in pregnancy by the FDA.
Regarding steroids, there are few reports on major fetal risks, premature rupture of the membranes, and intrauterine growth retardation.27 Prednisone is considered a class B drug in terms of its risk for pregnancy by the FDA.
In general, azathioprine is considered relatively safe during pregnancy in transplant populations, although, it is considered a class D drug by the FDA as a result of reports of congenital malformation in some exposed infants.
Mycophenolate mofetil has been shown to be potentially teratogenic,28 but most of the data are related to kidney transplantation. Mycophenolate mofetil is considered therefore by the FDA to be a class D drug in terms of the risks associated with its use in pregnancy.
Sirolimus exposure during pregnancy has been reported in only 2 liver transplant recipients, so the data are relatively scant.28 Sirolimus has been designated as class C, albeit with less data available to assess outcomes during pregnancy.
Fetal and Maternal Outcomes
Fetal loss, prematurity, and low birth weight have been reported in women who have undergone transplantation, and maternal risks include hypertension, pre-eclampsia, gestational diabetes, and graft dysfunction. The rate of caesarean section is considerably higher in patients post–liver transplantation. It is crucial for posttransplant patients, who conceive to be managed by centers with multidisciplinary care teams including a liver transplant hepatologist and surgeon, an obstetrician, and a pediatrician.
Immunosuppressive Drugs and Breast Feeding
Most transplant physicians advise against breastfeeding because of concerns over the safety of neonatal exposure to immunosuppressive drugs. Corticosteroids, cyclosporine, and tacrolimus are excreted in breast milk, whereas no data have been reported for sirolimus. An interesting study was performed on 15 pregnancies post–liver transplantation in patients treated with tacrolimus. Maternal, cord, and neonatal blood and placental tissue were stored at, or shortly after, delivery for determination of tacrolimus levels. Mean tacrolimus concentrations were 4.3 ng/mL in the placenta versus 1.5, 0.7, and 0.5 in maternal, cord, and neonate plasma, respectively, and 0.6 in the initial breast milk. These neonates, however, were not subsequently breastfed, and as a result, little data have been accumulated on the safety or danger of neonatal exposure to the agents commonly used post-transplantation.29
QUALITY OF LIFE AND SEXUAL FUNCTION
The goal of liver transplantation is not only to ensure the survival of patients, but also to offer patients the opportunity to achieve a good balance between the functional efficacy of the graft and their psychological and physical integrity. Quality of life assessments are used to evaluate the physical, psychological, and social domains of health, which are seen as distinct areas that are influenced by a person's experiences, beliefs, expectations, and perceptions. Quality of life has emerged as a medical indicator in transplantation medicine too.30
Quality of life and sexual functioning have become very important in liver transplant recipients. Health issues, medications, aging, and psychological and social issues may affect posttransplant sexual health.
A meta-analysis performed by Bravata et al.31 showed a statistically significant improvement of sexual function after transplantation in 7 studies. Sexual activity was evaluated by Parolin et al.32 in 28 women who underwent liver transplantation, and it was shown that 70% of sexually active patients were satisfied by their sexual health (75% had weekly intercourse associated with orgasm in 70% of cases).
However, 2 more recent studies8, 33 described less favorable data. In the study by Ho et al.,33 32% of patients who underwent liver transplantation reported de novo sexual dysfunction after liver transplantation. Moreover, 23% of males and 26% of females reported decreased libido, and 33% of men and 26% of women reported having difficulty reaching orgasm with intercourse. In the second study,8 although 43% reported no decreased libido, 40% of patients who underwent liver transplantation reported a decreased frequency of sexual intercourse, and among men, partial and complete erectile dysfunction was reported by 20.6% and 34.3%, respectively.
Experience of the Padua Multivisceral Transplant Unit
At the Multivisceral Transplant Unit of Gastroenterology (Padua University Hospital, Padua, Italy), a cross-sectional study was performed with the aim of assessing the prevalence of sexual dysfunction in patients with cirrhosis and in a cohort of liver transplanted patients. Participants included 79 patients with cirrhosis (35 men and 44 women, mean age = 53.8 ± 8.3 years) and 98 liver transplant patients (44 men and 54 women, mean age = 55.9 ± 9.6 years, mean time from transplantation = 5.7 ± 4.1 years). Demographic characteristics and clinical variables were comparable between the 2 groups of patients. Severity of liver disease (Child-Turcotte-Pugh and MELD scores) was assessed in all patients with cirrhosis. All patients underwent serum sexual hormone level quantification, and validated questionnaires to assess sexual dysfunction (Female Sexual Function Index and International Index of Erectile Function), depression (Beck Depression Inventory), and quality of life [Short Form (36) Health Survey)] were administered.
Among women, patients with liver cirrhosis showed significantly lower levels of total testosterone (P = 0.0001) and higher levels of prolactin (P = 0.006) and delta-4-androstenedione (P = 0.0002) in comparison with patients who underwent transplantation (Table 3). The prevalence of sexual dysfunction was lower in patients who underwent transplantation in comparison with patients with cirrhosis, although it was not statistically different (65% versus 60%, P = not significant; Fig. 1).
Table 3. Sexual Hormone Levels in Women with Liver Cirrhosis and After Liver Transplantation: The Experience at Padua University Hospital (Padua, Italy)
Sexual dysfunction was correlated with older age (P = 0.009) in female patients with cirrhosis, whereas after transplantation, it was greater in patients with depression (P = 0.003) and reduced quality of life (P = 0.023).
Among men, patients with liver cirrhosis showed significantly higher levels of prolactin (P = 0.00001) and sexual hormone binding globulin (P = 0.0006) in comparison with liver transplant patients (Table 4). The percentage for severe erectile dysfunction was significantly greater in patients with cirrhosis versus liver transplant patients (43% versus 22%, P = 0.04; Fig. 2). Moreover, a worse International Index Erectile Function score was seen in patients with cirrhosis versus patients who underwent transplantation (14.3 versus 19.5, P = 0.04). Sexual dysfunction correlated with old age (P = 0.03), whereas after transplantation, it was greater in patients with depression (P = 0.02). We concluded that, for both men and women with liver cirrhosis, sexual dysfunction is confirmed, but surprisingly, it is still present after liver transplantation, with depression being the major risk factor.
Table 4. Sexual Hormone Levels in Men with Liver Cirrhosis and After Liver Transplantation: The Experience at Padua University Hospital (Padua, Italy)
The impact of liver transplantation on sexual dysfunction is still an open issue. The improvement is significant and perceived after surgery, but despite these good results, overall sexual function and quality of life after liver transplantation seem lower than expected. This discrepancy may be related to medical complications after surgery and to psychological difficulties in psychosocial adjustments and coping strategies, but it may also be related to the limits of the research in the field of sexuality and quality of life following organ transplantation. More detailed and comprehensive data are needed in the field of sexual function after transplantation, and new strategies are needed to support and inform patients on the waiting list and after liver transplantation.