Long-Term Follow Up of the Erectile Function of Testicular Cancer Survivors

Abstract

Introduction

Alongside cardiovascular disease, cancer is currently the main cause of mortality worldwide. Italian cancer registers show that nearly 5% of the population has received a diagnosis of cancer (1). However, modern treatments mean that the life expectancy of about 60% of juvenile and young adult cancer survivors is comparable to that of the general population.

Men in reproductive age are mainly affected by testicular cancer (TC) and lymphomas, but despite the high incidence, their 5-year survival rates are above 80–90% (2, 3). These cancer survivors will therefore have to live with the long-term physical and psychological consequences of both their treatments (surgery, chemotherapy, radiotherapy) and the diagnosis itself (4, 5). This has important health, social and economic repercussions, as these long-term consequences affect men in their working and reproductive years, affecting their physical capabilities as well as their reproductive and sexual health. According to the WHO, reproductive health is defined as a “state of complete physical, mental and social well-being and not merely the absence of disease or infirmity, in all matters relating to the reproductive system, and to its functions and processes” (6). Sexual health should in fact be considered as a complex interaction of multiple factors including social and cultural aspects, individual experiences, and self-image. Cancer and its treatments should certainly be considered as capable of disrupting sex life, but many patients find it difficult to discuss these problems and there is a lack of consensus on valid outcome measures for assessing sexual function in cancer patients on the basis of a broader definition of sexual health (7)—issues yet to be faced in common practice or research.

Most knowledge of male sexual dysfunction after cancer pertains to prostate cancer after invasive surgical procedures and hormonal treatments: however, this is not representative of other situations (8). The sexological features of testicular cancer have been investigated by several authors, revealing associations with perceived loss of masculinity and sexual function, which paves the way for psycho-organic sexual dysfunctions (4). Orchiectomy itself can alter the perception of body image, potentially manifesting as reduced libido and sexual gratification linked to the psychological stress of not “being normal” (9). The cancer diagnosis itself is a moment of intense psychological distress and, although literature reports vary widely, about one-third of patients with testicular cancer report erectile dysfunction and/or ejaculation disorders (10). Invasive and destructive surgery such as retroperitoneal lymph node dissection increases the frequency of such dysfunctions (10–12). However, most data focus on either the short- or the long-term consequences of therapy and reports of thorough longitudinal follow-up from diagnosis to long-term survivorship are rare. The aim of this study is to evaluate the effect of TC after orchiectomy and provide a complete follow-up in order to highlight possible short- and long-term sexological changes after treatment.

Materials and Methods

Results

Discussion

The trend of reduced mortality for various cancers, including testicular cancer, has increased clinicians' awareness of the importance of long-term quality of life after surgery and chemo- and radiotherapy. Recent literature has focused on cancers involving the testes and genitalia (8, 12, 14, 15), but sexual function in male survivors of other frequent cancers has also been investigated (16, 17). In general, while TC survivors maintain or recover a good quality of life, investigation of their sex life reveals marked changes (18–20). Carpentier et al. highlighted that the diagnosis and therapy stages are associated with peak levels of anxiety and concern, which then drop in the post-treatment period. Similarly, stress-related central inhibition of sexual function results in a rise in libido, erection, and ejaculation disorders during cancer treatments (4). In fact, sexual dysfunctions in TC patients may arise from a combination of treatment-related physical side effects (genital mutilation, reduced testosterone levels, chronic pain, and other residual side effects) and psychological vulnerability (anxiety, fear, mood disorders, etc.) (Figure 2) (21). A possible underlying cause may be the induction of iatrogenic hypogonadism: in fact, orchiectomy, chemotherapy, and radiotherapy may all induce gonadal dysfunction. Our group recently found that a cohort of orchiectomized TC patients prior to cancer treatment had increased levels of gonadotropins and reduced testosterone in comparison with healthy controls, albeit still within the normal range (22). Some authors have shown that gonadotropin alterations persist after chemotherapy, while about 10% of patients may suffer from low total testosterone levels after treatment or have a higher risk of late onset hypogonadism (20, 23–26). However, other authors found that chemotherapy had only mild effects on hormone levels (27, 28). In contrast, radiotherapy may affect testosterone levels for up to 5 years in TC patients who received testicular irradiation for contralateral carcinoma in situ (29), but direct testicular irradiation is not a standard treatment for TC patients and current radiotherapy protocols probably have only a minor effect on testicular function (20). In any case, whether or not altered gonadotropin and testosterone levels are the only determinant of sexual dysfunctions in TC patients is still under debate. The already cited study by Huddart et al. found that about 10% of post-therapy TC patients had biochemical hypogonadism, with worse sexual function than observed in non-hypogonadal TC survivors (20). However, a later study by Lackner et al. (30) found a higher percentage of post-treatment hypogonadism (26%). These authors could not identify an unambiguous threshold level for testosterone associated with the onset of sexological symptoms, and hypothesized that each patient might have an individual threshold (30). In 2009, Eberard et al. published a caseload of 129 TC survivors 3–5 years post-therapy compared to an age-matched group of men without cancer, observing that TC survivors had a higher likelihood of low sexual desire (OR 6.7) and erectile dysfunction (OR 3.8) compared to controls, but that these conditions could not be predicted from the presence of hypogonadism (31). However, these results are limited by the lack of the pre-treatment status of the TC patients. Subsequent studies also failed to find a clear association between sexual dysfunctions and biochemical hypogonadism (28, 32–34). In conclusion, most of the literature evidence suggests that the high prevalence of sexual dysfunctions cannot be justified by the relatively low prevalence of biochemically detected hypogonadism. Another hypothesis could link sexual dysfunctions to specific treatment modalities. The side effects of several chemotherapy drugs include endothelial damage, angiopathy, and peripheral neuropathy, which may be linked to erectile and ejaculatory disorders (35, 36). Radiotherapy can cause sexual dysfunctions by inducing damage to the cavernous nerve and/or progressive fibrosis of the cavernous tissue and endothelial damage, which can become clinically evident through the onset of erectile dysfunction even several years post-treatment (37). However, the literature data are inconsistent, as several studies report no significant associations between sexual dysfunctions and specific treatment modalities (31), while others report the significant influence of either chemo- or radiotherapy (14, 15, 32, 38). The reason for this variability could be the use of different combinations of these therapies with different surgical procedures (tailored to the patient in relation to various clinical parameters such as stage, etc.), while individual variability might also induce different outcomes. Kim et al. reported that surgery combined with chemotherapy produced a higher incidence of reduced libido and ejaculatory disorders, while surgery combined with radiotherapy was followed by a greater incidence of erectile dysfunction (32). More recently, Bandak et al. observed that each treatment modality carried an increased risk of erectile and orgasmic dysfunctions, with multimodal treatment associated with the highest risk (15). Invasive surgical procedures such as retroperitoneal lymph node dissection are known to have a strong impact on sexual function (especially ejaculatory and orgasm disorders and impaired satisfaction) (12). Several studies have confirmed a worse sexological outcome after retroperitoneal surgery (lymph node dissection and/or re-surgery for relapse after chemotherapy) as a consequence of ejaculatory nerve damage during the procedure (10, 12, 21, 39, 40). Another issue is the trend of sexual dysfunction over time in TC survivors, as most literature studies are cross-sectional and only a few longitudinal studies are available. We currently expect a higher incidence of SD soon after the orchiectomy and the end of cancer treatment. Tuinman et al. found low IIEF scores post-orchiectomy and 3 months post-treatment, with significant improvements after 1 year of follow-up (41). These results were comparable to those of other studies focusing on SD within the first year after treatment (5, 42, 43). Long-term pre- and post-therapy comparisons are rare. Aass et al. found that sexual problems persisted in about 30% of TC survivors 36 months post-treatment (39), while Böhlen et al. reported no significant pre- vs. post-therapy differences in sexual function after at least 32 months of follow-up (44). Despite the general agreement on the presence of sexual dysfunctions in TC survivors, the absence of longitudinal long-term follow-up and the lack of standardization in the measurement of sexual function limit the assessment of their true patient burden. Data comparison and generalization are difficult, as different papers use a variety of tools and methods to evaluate sexual function. Moreover, in common with most sexological questionnaires, IIEF is poor at discriminating to what extent sexual dysfunctions are secondary to the organic sequalae of cancer treatments (45). In accordance with most of the available literature data, our results clearly show that TC patients undergoing orchiectomy and chemotherapy suffered from a higher degree of sexual dysfunctions than a control population of cancer-free subjects. These mainly presented as erectile dysfunctions, but also as impaired sexual desire and satisfaction. The incidence of orgasmic dysfunction did not differ significantly from controls. It is worth noting that the presence of these sexual dysfunctions at the baseline suggests that they might be induced by orchiectomy. However, it is difficult to find a biological relationship. We found a lower incidence (about 4%) of biochemical hypogonadism at the baseline (total testosterone < 8.0 nmol/l) than in other reports, but like them, we found no significant correlation with sexual function domains (20, 30, 31). This suggests that sexual dysfunctions are not explained by abnormal hormone levels consequent to orchiectomy and might instead be more closely associated with a psychological burden in these patients, which might coexist and be synergistic with treatment-induced hypogonadism. As the testicles are associated with masculinity, orchiectomy might well induce changes in body perception. In a caseload of 407 TC patients, Rossen et al. observed that about 17% had a reduced perception of masculinity induced by orchiectomy. This was associated with a 9-fold increased risk of erectile dysfunction and a 15-fold increased risk of sexual discomfort (10). Wortel et al. reported that after orchiectomy, up to 50% of patients might complain of a distorted perception of body image (42). All of our patients underwent the insertion of a testicular prosthesis. This may have positively influenced their body perception, as suggested in a study by Catanzariti et al. (43), but whether and to what extent this might have contributed to the improved IIEF-15 scores in our study is unknown, and should be investigated in further studies. We also detected a significant improvement in erectile function post-therapy. Although some degree of erectile dysfunction persisted at all time points, the incidence constantly dropped in the first 2 years after treatment (up to T4) and the IIEF-15 erectile dysfunction scores improved and were comparable to the controls 1 year after treatment (T2). There was also a trend of improvement in sexual desire and in both intercourse and general satisfaction, but follow-up showed that they remained significantly worse than in the controls. To our knowledge, the present study is the longest monocentric follow-up currently available for the sexological evaluation of TC patients. Unfortunately, the generalizability of data comparisons against healthy controls might be reduced for long term follow-up, as the increased percentage of patients with erectile dysfunction at T5 and T6 may simply be due to their increased age and the consequent possible onset of other factors (hypertension and other cardiovascular diseases, use of medications, etc.) increasing the incidence of sexual dysfunctions, independently of TC and its treatments.

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Figure 2

Determinants of sexual dysfunction in testicular cancer survivors.

In conclusion, our data, from a large caseload compared to a control group of similar age and strengthened by the use of a validated psychometric tool, indicate that TC patients need adequate sexological counseling following diagnosis/orchiectomy and prior to chemotherapy. Discussing these aspects with patients could help them to cope with the disease and to understand that their erectile function should improve within a year after the end of treatment. Future studies should identify subjects who are more likely to suffer from SDs, thus permitting the better follow-up of these patients and enabling them to be offered all the support they need to maintain a satisfactory sex life and, consequently, a good general quality of life.

Data Availability

The datasets for this manuscript are not publicly available. If required, the data are available in our database upon request. Requests to access the datasets should be directed to ti.1amorinu@iloap.alletanod.

Author Contributions

FL, FP and DP conceived the study; FP and FL wrote the article; FP, AP and FC acquired and analyzed the data; FL, FP and DP contributed to data interpretation; AR and AL manuscript revision.

Acknowledgments

Footnotes

References