Male infertility in cancer patients: Review of the literature

The number of men surviving cancer at a young age has increased dramatically in the past 20 years as a result of early detection and improved cancer treatment protocols; more than 75% of young cancer patients nowadays are long‐term survivors. Quality of life has become an important issue in childhood and adult cancer patients. The commonest cancers in patients of reproductive age are leukaemia, Hodgkin's lymphomas and testicular germ cell tumors. Fertility is often impaired after chemotherapy and radiation therapy. Cryopreservation of semen before cancer treatment starts is currently the only method to preserve future male fertility. In some malignancies, especially in germ cell tumors, sperm quality is already abnormal at the time of diagnosis. In approximately 12% of men, no viable spermatozoa are present for cryopreservation before the start of chemotherapy. Cytotoxic therapy influences spermatogenesis at least temporarily and in some cases permanently. The amount of damage inflicted by chemotherapy on spermatogenesis depends on the combination of drugs used and on the cumulative dose given for cancer treatment. Alkylating agents, such as cyclophosphamide and procarbazine, are most detrimental to germ cells. Radiation therapy, especially whole‐body irradiation, is also associated with the risk of permanent sterility. Besides the cancer treatment, tumor type and pretreatment fertility are of prognostic value for future fertility in male cancer survivors. After cancer treatment, many men need artificial reproductive techniques to achieve fatherhood; usually in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is indicated for successful treatment. About 15% of men will use their cryopreserved semen because of persistent azoospermia after cancer treatment. Treatment results with cryopreserved semen are generally good and comparable to general IVF and ICSI results. So far, no studies have reported an increased rate of congenital abnormalities or malignancies in children born from fathers who had cancer treatment is the past, but close follow up is warranted, especially in children born after IVF/ICSI.     

Sexual function and fertility after treatment of testicular cancer

As a result of the introduction of effective cisplatin-based chemotherapeutic regimens into the clinical routine, even patients with metastatic testicular cancer at initial diagnosis can be cured of their disease. Sexual dysfunction and infertility are common long-lasting sequelae in testicular cancer survivors, affecting approximately 20% of patients after the application of the different treatment modalities currently available for the treatment of early and advanced clinical stages, including retroperitoneal surgery and systemic chemotherapy. Accordingly, it has been demonstrated that fertility distress and sexual disturbances, the latter occurring in only a minority of patients after surgical or chemotherapeutic treatment of testicular germ cell tumours, substantially alter the patients' quality of life. It is even worse because testicular cancer mostly affects men in the prime of their physical, sexual and reproductive function. Although semen quality is frequently poor at initial diagnosis and further deteriorates after orchiectomy, probably because of structural abnormalities in the remaining contralateral testicle, the advent of intracytoplasmatic sperm injection promises a fertile future to most patients, even if only a few sperms are present in the ejaculate. Further long-term investigations should be initiated to clarify the impact of the different treatment modalities on fertility and sexual life. The main objective should be the identification of patients who are at increased risk of developing therapy-related physical and psychological problems.     

Fertility in the testicular cancer patient

Conclusions Infertility remains a major complication of testicular malignancy. Although the risk of testes cancer is small, the disease affects men in their peak reproductive years and fertility issues will be important to the majority of patients. As mortality from testes cancer falls, more attention is being focused on reducing morbidity, including infertility.There is no reliable way to predict which patients will retain or recover fertility potential after treatment, and the adverse effect on fertility should be considered in all patients. Recovery of spermatogenesis may continue for up to 5 year following treatment, but a failure to improve after 2–3 years implies a poor prognosis.Treatment will depend largely on the semen quality at the time of evaluation. Azoospermia and a markedly elevated FSH level indicate spermatogenic failure. Oligospermic patients will likely require some form of assited reproductive technique, although chances of pregnancy will continue to be less than 25% following either artificial insemination or IVF. Normospermic patients should have sperm-function testing and antisperm antibody assays performed. A thorough evaluation of the woman should also be carried out.More research needs to be done on cytoprotection of the seminiferous epithelium from the effects of chemotherapy and radiotherapy before it can be recommended in the clinical setting.     

Fertility after chemotherapy for testicular cancer

Disseminated testicular cancer has largely become curable with cisplatin-based chemotherapy. The prospect of fertility after treatment is an important consideration for both patients and clinicians. While there may be an irreversible impairment of spermatogenesis at a cumulative cisplatin dose of greater than 400 mg/m2, a low sperm count does not necessarily appear to prevent fatherhood. This review summarizes currently available data on the effects of chemotherapy on male fertility and steps that can be taken to preserve fertility in this patient population.     

Gonadal dysfunction in male cancer patients before cytotoxic treatment

Male patients diagnosed with cancer are often referred for semen cryopreservation before gonadotoxic treatment but often have low semen quality. The aim of this study was to evaluate which type of cancer affects gonadal function and proposes a risk factor for low pre-treatment semen quality. Between January 1983 and August 2006, 764 male cancer patients were referred for semen cryopreservation prior to chemotherapy and radiotherapy. We compared semen characteristics and reproductive hormones between different groups of cancer patients. In addition, we evaluated the role of tumour markers in patients with testicular germ-cell tumours (TGCT) on fertility. Abnormal semen parameters were found in 489 men (64%) before cancer treatment. Patients with TGCT and extragonadal germ-cell tumours had significantly lower sperm concentrations and inhibin B levels than all other patient groups. No semen could be banked in 93 patients (12.2%). Eight hundred and thirty-nine of 927 (90%) produced semen samples were adequate for cryopreservation. Inhibin B in all groups showed to be the best predictor of semen quality. Although pre-treatment raised tumour markers were associated with a decrease in inhibin B and increased follicle stimulating hormone, both predictive for low semen quality; no direct linear association could be found between raised beta-HCG, alfa-fetoprotein and semen quality. Only 1/3 of cancer patients had normal semen parameters prior to cancer treatment. Patients with TGCT and extragonadal GCT have the highest risk for impaired semen quality and gonadal dysfunction at the time of semen cryopreservation.     

Is routine pre-treatment cryopreservation of semen worthwhile in the management of patients with testicular cancer?

Post-treatment fertility was evaluated in 147 patients with testicular cancer, All had pre-treatment sperm cell analysis following orchiectomy during the years 1979 to 1987. For only 17 patients was the question of future fertility of no importance. Pre-treatment semen cryopreservation was requested by 91 patients, but poor semen parameters made this procedure impossible in 38. Of 99 evaluable patients, 44 had a post-treatment sperm count greater than or equal to 10 x 10(6)/ml and 22 of these fathered a child after treatment. Post-treatment fertility was observed to the same degree in patients who had pre-treatment semen cryopreservation as in those in whom this procedure could not be performed. Four of 53 patients used their deep-frozen semen but only 1 pregnancy resulted. The intensity of treatment, especially the extent of retroperitoneal surgery, had a significant effect on post-treatment fertility in the individual patient. Pre-treatment cryopreservation of semen may be psychologically useful in patients with newly diagnosed testicular cancer, but its clinical significance is doubtful.     

Fertility treatment in male cancer survivors

The present study reviews the use of assisted reproductive technology in male cancer survivors and their partners. As antineoplastic treatment with chemotherapy or radiation therapy, has the potential of inducing impairment of spermatogenesis through damage of the germinal epithelium, many male cancer survivors experience difficulties in impregnating their partners after treatment. The impairment can be temporary or permanent. While many cancer survivors regain spermatogenesis months to years after treatment, some become infertile with a-, oligo- or azoospermia. An option to secure the fertility potential of young cancer patients is to cryopreserve semen before cancer treatment for later use. A desired pregnancy may be obtained in couples where the husband has a history of cancer, using assisted reproductive technology with either fresh or cryopreserved/thawed semen. Successful outcomes have been obtained with intrauterine insemination (IUI) as well as in vitro fertilization (IVF) with or without the use of intracytoplasmic sperm injection (ICSI). In conclusion, male cancer survivors and their partners who have failed to obtain a pregnancy naturally within a reasonable time frame after end of treatment should be referred to a fertility clinic.     

Do malignant diseases affect semen quality? Sperm parameters of men with cancers

The advent of modern treatments together with the improvement of the surgical techniques has significantly increased 5‐year survival rates of young patients with cancer. Although the deleterious effects of chemotherapy and radiation are well documented, controversies exist about the effect of cancer itself on semen parameters before treatment. We collected data on 236 patients representative of different types of cancers reoffered at our institution for sperm cryopreservation with the aim to correlate the pre‐freeze semen parameters with type of cancer, disease stage and with semen quality of 102 fertile and healthy men. The median baseline semen parameters of all our patients with cancer are placed above the 5th percentile of the World Health Organization reference value, but the type of cancer may impact the sperm parameters. In testicular tumours and in Hodgkin lymphoma, we show a semen concentration statistically lower than in the fertile population, while in patients with other cancers, there is no difference with the healthy men. We found no correlation between semen quality and disease stage. Eighty‐six per cent of our patients do not have children at the time of semen cryopreservation, and the only established clinical option for preserving fertility of these men is cryopreservation of spermatozoa.     

DNA flow cytometry in sperm cells from testicular cancer patients. Impact of different treatment modalities on spermatogenesis

In 77 patients with testicular cancer, sperm cell density was evaluated before and after treatment together with the following parameters as recorded by DNA flow cytometry: the percentage of condensed and non-condensed haploid sperm cells, and the number of non-haploid cells. The patients received either abdominal radiotherapy, cisplatin-based combination chemotherapy (+/- surgery) or did not undergo antiproliferative treatment at all. Ejaculates with a low sperm cell density had high numbers of non-condensed haploid and non-haploid cells, whereas the percentage of condensed haploid cells was decreased. However, even 'azoospermic' semen samples (by light microscopy) contained haploid cells indicating ongoing sperm cell production. One year after radiotherapy there was a significant decrease in the sperm cell density and the number of condensed haploid cells. Chemotherapy led to a significant reduction of sperm cell density evaluated 1 year after treatment. Three years after the diagnosis of testicular cancer, sperm cell production had recovered in most patients. In patients who did not have radiotherapy or chemotherapy the median density of sperm cells 3 years after treatment significantly exceeded the corresponding figure from the pretreatment situation. A low pretreatment percentage of condensed haploid cells (less than or equal to 90%) was correlated with the lack of 1-year recovery of sperm cell production. It is too early to state whether longitudinal flow cytometric data from ejaculates in testicular cancer patients yield clinically valuable information, in addition to that obtained by light microscopy. From this preliminary observation it seems that DNA flow cytometry in ejaculates from testicular cancer patients may give valuable clinical information about sperm cell production following treatment.     

Serum creatinine and cholesterol levels of testicular cancer patients in long-term follow up

PURPOSE: Most patients with advanced testicular cancer can be cured with cisplatin-based chemotherapy. Therefore, the long-term effects of the treatment are clinically important. In the present study, we evaluated the serum creatinine and cholesterol levels of long-term survivors of testicular cancer. METHODS: Serum creatinine and cholesterol levels were determined in 23 testicular cancer patients who had received cisplatin-based chemotherapy more than 5 years earlier. They were compared with a control group of 16 patients who did not receive chemotherapy. In addition, follow-up data of beyond 10 years after the initial treatment was obtained from 17 patients. We also analysed the trends of both serum creatinine and cholesterol determinations over 10 or more years using a generalized linear model. RESULTS: There was no significant difference in the serum creatinine and cholesterol levels 5 years after the treatment between the chemotherapy and control groups. Analysis using a generalized linear model showed a significant trend toward an increase in serum creatinine in patients who had developed renal dysfunction during chemotherapy (P = 0.0024). The elevation of the serum creatinine level was mainly observed during the first 5 years. In addition, a significant trend toward an increase in serum cholesterol was revealed in both the chemotherapy and control groups. CONCLUSION: Patients who have developed renal dysfunction during chemotherapy may be at risk of gradually increasing serum creatinine levels even after it has become normal. Although further analysis is needed, we recommend long-term follow up in the survivors of metastatic testicular cancer patients treated with cisplatin-based chemotherapy.     

Chemotherapy in the post-MVAC era: the case for adjuvant chemotherapy

Radical cystectomy for muscle invasive and locally advanced bladder cancer is the standard treatment modality in most of the Western industrialised countries. Rates of perioperative mortality from radical cystectomy have decreased to less than 2% over the past two decades due to advances in surgical technique and perioperative care. However, at least 40% of patients with pT3 bladder cancer and 70% of patients with lymph node-positive disease develop tumour recurrence after radical treatment within the first 5 years when treated with radical cystectomy alone. After the efficacy of combination chemotherapy for metastatic urothelial cancer using methotrexate, vinblastine, adriamycin and cisplatin (MVAC) was first described in 1985, several cisplatin-based systemic regimens have been investigated as adjunctive treatment before or after therapy for locally advanced bladder cancer by radical surgery or radiation therapy. Three randomised studies have reported superior results of postoperative adjuvant systemic chemotherapy compared to radical cystectomy alone for locally advanced bladder cancer. All three studies demonstrated a significant survival benefit for bladder cancer patients receiving adjuvant combination therapy. Studies have been criticised for small patient numbers and statistical shortcomings. New effective antineoplastic agents, such as paclitaxel and gemcitabine, have evolved during the past decade as promising substances for the treatment of urothelial cancer. This article reviews adjuvant studies from the era of MVAC combination chemotherapy, as well as contemporary studies that discuss new antineoplastic agents for systemic adjuvant chemotherapy of locally advanced bladder cancer.     

Treatment of patients with metastatic germ cell tumors relapsing after high-dose chemotherapy

With the use of cisplatin-based combination chemotherapy, metastatic testicular germ cell tumors can be cured in 70–80% of patients. Patients refractory to cisplatin-based chemotherapy have a very poor prognosis. Several mechanisms have been discussed for the development of platinum resistance such as a decreased intracellular concentration of the drug, increased repair of the drug induced damage, or an altered apoptotic response to this damage. Various chemotherapeutic agents have been evaluated in intensively pretreated or cisplatin-refractory patients. Neither the antracyclines nor vinorelbine, bendamustine, topotecan, nor biological agents such as suramin and retinoic acid have demonstrated clinical activity. Paclitaxel has been evaluated at different doses and schedules and yielded a response rate of 21% (range 11–30%) with individual patients achieving complete remissions. This has led to the inclusion of paclitaxel in salvage regimens in combination with cisplatin and/or ifosfamide. Two recent studies have evaluated gemcitabine in refractory germ cell tumors, demonstrating a response rate of 17% (95% CI: 7–28%) in 52 intensively pretreated patients, two-thirds of whom had relapsed after previous high-dose chemotherapy plus autologous stem cell transplantation. The nonhematologic toxicity of weekly gemcitabine at doses of 1000–1250 mg/m² was tolerable and hematologic side effects included thrombocytopenia in approximately 20% of patients. Ongoing studies in refractory germ cell tumors performed by the German Testicular Cancer Study Group (GTCSG) are evaluating oxaliplatin, a platinum derivative with incomplete cross-resistance to cisplatin. Future trials combining new active agents may make it possible to test the use of alternating treatment strategies in patients with “poor prognostic” disease or as salvage treatment. It is hoped that the increase in knowledge of the molecular mechanism of testicular cancer may lead to the development of new therapeutic options.     

Long-term survival under maintenance gemcitabine chemotherapy for metastatic transitional cell carcinoma

We report a case of a 74-year-old patient who received 41 courses of maintenance therapy with gemcitabine over a length of 28 months for metastatic transitional cell carcinoma. One year earlier the patient had received three cycles of adjuvant cisplatin-based combination chemotherapy after nephro-ureterectomy for a locally advanced urothelial cancer of the right renal pelvis. This case demonstrates a paradigm shift in the palliative treatment of advanced urothelial cancer, with the implementation of more tolerable agents such as gemcitabine. Even elderly patients with impaired renal function may benefit in terms of tumor reduction and survival from systemic chemotherapy, which may be applied over a prolonged period of time.     

Perioperative immunotherapy for muscle-invasive bladder cancer

Radical cystectomy is the standard of care treatment for patients with localized muscle-invasive bladder cancer (MIBC). However, patients with MIBC experience high rates of relapse despite primary therapy, and perioperative strategy is an important treatment option. Cisplatin-based neoadjuvant chemotherapy was associated with improved prognosis, and adjuvant chemotherapy is also an important option for selected patients. However, perioperative chemotherapy is not effective in some patients. Moreover, the currently recommended perioperative treatment is cisplatin-based chemotherapy; approximately 50% of the patients are ineligilble for cisplatin treatment owing to various reasons such as medical comorbidities, poor performance status, and renal insufficiency. The recent success of treatment with immune checkpoint inhibitors (ICIs) suggests that ICIs is the new standard therapy for patients with metastatic bladder cancer. Furthermore, ICIs showed more favorable toxicity profiles than conventional cytotoxic chemotherapy. These results indicate that ICIs may play a role in the treatment of muscle-invasive disease, and many recent studies have been conducted in a perioperative setting. The present review aims to summarize and discuss the current perioperative strategy of immunotherapy focused on ICIs based on recent ongoing clinical trials.     

Diagnostic value of the zona-free hamster oocyte penetration test and sperm movement characteristics in oligozoospermia

A group of 27 oligozoospermic patients were followed up for 4.2 +/- 1.1 years in a prospective study designed to determine which aspects of semen quality are of value in the diagnosis of fertility. The semen analysis included the zona-free hamster oocyte penetration test, the assessment of sperm movement characteristics by time exposure photomicrography and a conventional semen profile. During the follow up period, 7 patients (25.9%) initiated a pregnancy. The identity of these fertile subjects could not have been ascertained by any single criterion of sperm movement or any feature of the conventional semen profile. The zona-free hamster egg penetration rates were also of little value in this respect since 4 of the 7 fertile patients scored 0% in this assay. Using a multivariate discriminant analysis, however, a combination of 7 criteria was identified, including hamster oocyte penetration and elements of both sperm movement and the semen profile, which could predict the fertility of these patients with 85.2% accuracy.     

Semen quality in sub-fertile range for a significant proportion of young men from the general German population: a co-ordinated, controlled study of 791 men from Hamburg and Leipzig

Population studies have shown that a high proportion of Nordic men may have so poor semen quality that they can be classified as sub-fertile according to international standards. A question is whether the Nordic data are specific for the Nordic countries or they should be seen as an expression of a general trend in Europe. We therefore carried out a prospective study of semen quality of young men raised in the former East Germany (Leipzig) and West Germany (Hamburg). To enable inter-regional comparisons, we utilized a common European research protocol previously used in studies in the Nordic-Baltic region. Three hundred and thirty-four young men representative of the general population from Hamburg, and 457 from Leipzig delivered semen samples, underwent physical examinations and provided information on life-style and reproductive health parameters. The study period in Hamburg was February 2003--July 2004, and in Leipzig July 2003--April 2005. No significant differences were observed in sperm concentration (median 46, 42, and 44 million/mL for men from Hamburg, Leipzig and the combined Hamburg-Leipzig group respectively) or total sperm count (154,141 and 149 million), whereas the differences for morphologically normal spermatozoa (9.4 and 8.4%) and motile spermatozoa (67 and 81%) were significantly different. Previously published studies have shown reduced fertility with decreasing sperm concentrations below 40-55 millions/mL and normal sperm morphology below 9-19%. Thus, a large fraction of young German men seem to have impaired semen quality that may reduce their natural fertility. However, it remains to be investigated to what extent poor semen quality contributes to the low German fertility rates.     

Individualized management of advanced bladder cancer: Where do we stand?

Despite recent progress in the development of novel targeted therapies in various malignancies, the management of advanced urothelial cancer has changed little over the past 2 decades. Comorbidities inherent to patients with bladder cancer often preclude the use of standard cisplatin-based chemotherapy and underscore the need for individualized treatment recommendations and the development of more effective therapies. This review discusses current issues relevant to the management of patients with locally advanced and metastatic urothelial carcinoma of the bladder and highlights recent advances in defining molecular aberrations that may ultimately lead to personalized therapeutic decision making.     

Experience in vibratory and electro-ejaculation techniques in spinal cord injury patients: a preliminary report

More than 90 per cent of complete spinal cord injury patients have major fertility problems, depending upon the site and type of injury. During the last 5 years 34 patients were treated by vibratory and/or electrostimulation at our center, and semen was produced in all but 5. In 8 patients ejaculation was attempted by vibratory stimulation alone and in 22 electrostimulation also was used. Vibratory stimulation is the easier and less cumbersome of the 2 methods. No major side effects were noted with either technique. Stimulation was performed by a rectal electrode incorporated in a silicone finger glove with a current of 0.1 msec. in duration, a frequency of 30 Hz. and an average of 60 volts. Vibratory stimulation was applied to the frenulum and/or glans penis with a specially constructed vibrator at a frequency of 80 Hz. and a peak-to-peak oscillation of 1.6 to 2.4 mm. Semen obtained during the first 6 months after injury was not of a quality consistent with successful fertilization owing to poor motility. However, semen quality and motility were better in patients who had been injured for more than 6 months. Repeated electro-ejaculation did not improve the quality of semen. The effects of bladder outlet surgery and autonomic blockers were noted in 5 patients.     

Clinical study of infertile males with varicocele showing no typical radionuclide blood pooling on dynamic image of scrotal scintigraphy

A clinical study was done of 19 patients in our male infertility clinic, who were diagnosed as having a varicocele and showed atypical radionuclide accumulation in the dynamic image of scrotal scintigraphy. The semen quality was good in 26 percent and poor in 42 percent. Patients with severe congestion in the varicocele tended to be small in number. The dynamic images of the varicoceles were classified into two groups: one group with no radionuclide accumulation, and one group with patchy radionuclide accumulations. Surgical treatment was performed in patients with poor semen quality or with a long infertility period. Neither improvement in the semen quality nor impregnation was achieved postoperatively in patients who had shown no accumulation of the radionuclide in the dynamic imaging. In patients who had shown patchy radionuclide accumulations, the postoperative results were good. We concluded that preoperative dynamic imaging of scrotal scintigraphy is a good means of estimating the postoperative prognosis of fertility.     

Effect of cancer therapy on pituitary-testicular axis

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men. Alkylating agents, such as cyclophosphamide and procarbazine, are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas are rendered permanently infertile. Treatment with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) appears to have a significant advantage in terms of testicular function, with a return to normal fertility in the vast majority of patients. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men with a recovery of spermatogenesis in about 50% after 2 years and 80% after 5 years. There is also evidence of chemotherapy-induced Leydig cell impairment in a proportion of these men, although this appears to be of no clinical significance in the majority of patients. The germinal epithelium is very sensitive to radiation-induced damage with changes to spermatogonia following as little as 0.1 Gy, and permanent infertility after fractionated doses of 2 Gy and above, whereas clinically significant Leydig cell impairment occurs rarely with doses of less than 20 Gy.