Approach to sexual dysfunction in patients with chronic liver disease

INTRODUCTION

Sexual dysfunction (SD) is a common but often under-recognized entity in patients with chronic liver disease (CLD) and cirrhosis. Reticence on the part of patients and providers to discuss SD contributes to less recognition and treatment of the problem, causing a resultant decline in quality of life. SD is used to describe multiple conditions, including low libido, inability to achieve orgasm, erectile dysfunction (ED) in men, and abnormal menstruation and ovulation in women.

PREVALENCE

Data regarding the prevalence of SD in patients with CLD are limited, with significant variability in the definitions used and methods of identification across studies. There are far more data on men than women. ¹

The degree of SD appears to correlate with the severity of liver disease. Scores indicating SD on the Liver Disease Quality of Life instrument, which evaluates 12 liver-specific domains ranging from physical symptoms to social and emotional functioning, worsen in those with Model for End-Stage Liver Disease scores >15. This correlation is particularly pronounced in male subjects. ² The prevalence of ED in patients with compensated cirrhosis is nearly 55%.^3–5 The prevalence and severity of ED progressively increase as Child-Pugh Scores and the number of hepatic decompensations increase. ⁶ A recent meta-analysis revealed a rise in the prevalence of ED from 54% in compensated cirrhosis to 88% in decompensated cirrhosis, with increasing severity of ED in decompensated patients. ⁷

For women, SD refers to a broad spectrum of conditions ranging from diminished sexual desire to derangements in menstruation. The literature on female SD in liver disease is limited. In those patients evaluated for liver transplantation, between 33% and 56% report no longer being sexually active, with decreased sexual desire in 41% and irregular menses or amenorrhea in 58%.^8–10 In women of reproductive age with end-stage liver disease, the prevalence rates of reproductive dysfunction, including amenorrhea and menstrual irregularity, range from 30% to 71%.^8,11

CAUSES OF SD

The development of SD in individuals with CLD is multifactorial, including, but not limited to, the etiology of the disease, cirrhosis-induced hypothalamic-pituitary suppression, portal hypertension, medications, and psychosocial factors.

Increased peripheral aromatization of androgens to estrogens is well established in cirrhosis, regardless of the etiology, in both men and women. ¹² This hyperestrogenic state is further exacerbated by elevated levels of sex hormone-binding globulin in cirrhosis, which preferentially binds testosterone over estradiol, resulting in a lower circulating level of bioactive testosterone.^6,12 Moreover, portal hypertension has been shown to increase the conversion of testosterone to estradiol, with studies demonstrating that an increasing HVPG independently correlates with the presence of ED.^6,13 The clearance of estradiol is typically normal in patients with CLD. ¹⁴

Hypothalamic-pituitary dysfunction plays a role in SD, but the pathogenesis is not fully elucidated. In men, high levels of luteinizing hormone have been observed in Child-Pugh classes A and B, and levels drop below normal in decompensated cirrhosis, indicating hypothalamic-pituitary dysfunction in severe disease. ¹⁵ Despite reduced testosterone in men with cirrhosis, follicle-stimulating hormone, and luteinizing hormone were inappropriately normal with an appropriate response to stimulation of exogenous gonadotropin-releasing hormone, indicating that normal feedback mechanisms, depicted in Figure 1 may be impaired. ¹⁶ Outside of hormonal disruptions, there are disease-specific direct toxicities resulting in primary hypogonadism, including alcohol’s direct effect on Leydig cells in the testes and iron accumulation in the testes in patients with hemochromatosis.^17,18

FIGURE 1.

HPA and sex hormone axis. (1) Hypothalamic-pituitary-adrenal (HPA) Axis (blue): CRH is released from the hypothalamus in response to stress. CRH then stimulates the pituitary glands to release ACTH, which in turn acts on the adrenal glands to release cortisol and activates a systemic stress response. Elevated cortisol levels act as a negative feedback mechanism on the hypothalamus, shutting down the HPA axis. (2) Sex hormone regulation (green): GnRH from the hypothalamus stimulates the pituitary to produce LH and FSH to stimulate the ovaries and testes. Subsequent testosterone release from the testes provides negative feedback inhibition to the hypothalamus and the pituitary gland, whereas the effects of estrogen release from the ovaries can be inhibitory or stimulating depending on the phase of the reproductive cycle. (3) Impact of chronic liver disease (red): Patients with liver disease have a hyperestrogenic state due to increased levels of SHBG preferentially binding testosterone, in addition to increased peripheral aromatization of androgens to estrogen and increased conversation of testosterone to estradiol in the setting of portal hypertension. Additionally, men with later stages of cirrhosis have lower LH, resulting in decreased stimulation of testosterone release in the testes. Similarly, low levels of LH and FSH can result in anovulation in women due to decreased progesterone secretion. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GnRH, gonadotropin-release hormone; LH, luteinizing hormone; SHBG, sex hormone-binding globulin.

In women with CLD, studies have shown derangements in luteinizing hormone, follicle-stimulating hormone, and gonadotropin levels. ¹⁹ The development of amenorrhea is not necessarily correlated with the severity or duration of liver disease. ¹⁹

Medications commonly used to manage cirrhosis can also contribute to SD. Spironolactone has a well-established dose and time-dependent antagonistic effect on androgen activity. β-blockers’ impact on SD, however, remains unclear. Despite a long-standing concern that β-blockers increase ED, a meta-analysis of β-blocker use in men with cirrhosis showed no increase in SD. ⁶

WORKUP

Screening for SD should be considered for all patients presenting for treatment of CLD, although it is rarely implemented in practice. There are several commonly used health-related quality of life questionnaires in hepatology, such as the Chronic Liver Disease Questionnaire and Short Form 36, which do not directly address SD. The Short Form Liver Disease Quality of Life Questionnaire limits the evaluation of SD to one domain.

For screening men, the International Index of Erectile Function, which addresses 5 domains of sexual function, should be used. In women, screening can be conducted using the Female Sexual Function Index, which evaluates 6 domains of sexual function. ¹

In patients who screen positive on either form, it is essential to consider concurrent or alternative causes of SD, which are outlined in Figure 2. Given the prevalence of metabolic diseases in patients with liver disease, screening for obesity, diabetes, associated neuropathy, and hyperlipidemia is recommended.^13,20 Other potential causes of SD, such as hypertension, peripheral vascular disease, hyperthyroidism, psychiatric disorders, and medication effects, should also be ruled out. Any of the listed conditions should be adequately treated prior to attributing SD to concomitant liver disease.

FIGURE 2.

Workup of sexual dysfunction in chronic liver disease. Abbreviations: FSFI, Female Sexual Function Index; IIEF, International Index of Erectile Function; SSRI, serotonin specific reuptake inhibitor.

All patients should undergo a genitourinary examination to exclude anatomic pathologies. In women, dyspareunia may be present in the setting of fibroids, endometriosis, or pelvic prolapse. ²¹ In men, Peyronie disease or cavernous fibrosis can contribute to ED. ²²

Testing for androgen deficiency is recommended by the American Urological Association in standard workup of ED, but there is no conclusive data on its utility in patients with liver disease. ²² While some groups recommend routine testing of sex hormone levels in men, there is insufficient data to support this practice or to guide the interpretation of sex hormone abnormalities in those with CLD. ¹⁰ As discussed earlier, regarding the causes of SD, sex hormone levels and the function of their feedback mechanisms can vary with the severity of liver disease, making them unreliable indicators of SD. Testing of hormone levels is not recommended in healthy women with SD and likely has little utility in patients with liver disease unless to confirm suspected early menopause in select patients. ¹

TREATMENT

Treatment of SD entails identifying the type of SD and addressing potentially contributing comorbidities or medications. Regarding targeted treatment, there is limited data to support the use of testosterone replacement therapy, and caution should be used in those with hepatic malignancies. ²³ Phosphodiesterase-5 inhibitors can be used for ED in men with Child-Pugh A or B, and some formulations have been shown to decrease portal hypertension. ²²

For women, there are limited targeted therapies available for low libido. Testosterone patches have been found to be effective in postmenopausal women with low libido, but safety and efficacy have not been established in women with cirrhosis. ²⁴ Hormonal replacement therapy has been found to be safe in women with compensated cirrhosis. ²⁵ Oral contraceptive medications may help with anovulation or amenorrhea and have been found to be safe in patients with even mild decompensated cirrhosis, with low estrogen and progesterone-only formulations preferred. Transdermal therapy and intrauterine devices have also been deemed safe contraceptive methods in patients with liver disease. ²⁵ It should be noted that patients with abnormal menstruation have a low likelihood of achieving pregnancy. In patients with menorrhagia, cirrhosis-related coagulopathy should be addressed and optimized, and iron should be supplemented and used as needed. ¹⁰

CONCLUSIONS

SD encompasses multiple conditions and impacts a large percentage of patients with advanced liver disease and cirrhosis. The etiology of SD is multifactorial, and targeted treatment options are currently limited. Screening for SD and identifying potential contributing factors should be performed in all patients. Standard of care for SD from the general population can be applied in most cases in patients with CLD, but there remains limited objective data on the efficacy and safety of many therapies.