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For several years, fertility disorders have been on the increase worldwide. These disorders affect both sexes, but are more pronounced in men; and in half of cases the etiology is unknown. The role of drugs in male infertility has been little studied to date. Most of the available data comes from experimental animal studies, with all their limitations. With the exception of a few drugs, such as certain anticancer agents, human data are rare. This article describes the mainly drugs known to have deleterious effects on male fertility, the mechanisms leading to these effects and methods used to assess the risk of drug-induced male infertility. It underlines the need for further work in experimental research, clinical trials and post-marketing surveillance to improve our knowledge of drugs that induce male infertility. Although these adverse effects are not life-threatening, they can have a significant impact on patients' lives., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

We reviewed the available animal and human reproductive function studies of recently approved noncytotoxic oncology drugs. We reviewed the oncofertility information in the prescribing information for the US Food and Drug Administration (FDA)-approved products and/or the product information and consumer medicine information for Therapeutic Goods Administration (TGA)-approved drugs of 32 novel oncology drugs approved between 2014 and 2018 in the United States and/or Australia supplemented by a literature review for additional reproductive effects. No human studies were available on the reproductive effects of all 32 drugs. A systematic literature review of animal reproductive toxicity studies provided only very limited data with nine drugs displaying impaired male fertility, three impaired female fertility, and nine producing impaired fertility in both male and female animals. Two drugs in the study are reported to have no demonstrable impact on fertility in animal reproductive toxicity studies and nine are reported to have unknown effects on fertility. Of the 32 newly listed drugs, only 4 had recommendations regarding potential human fertility risks and accordingly advised clinicians about fertility preservation procedures for patients. The lack of human data and limited animal reproductive toxicity data raises concerns about the potential impact of these novel oncology drugs on human fertility and reproductive function. Consequently, adequate oncofertility recommendations, including for fertility preservation procedures, counselling for psychological or cost implications, and future prognosis for fertility are hindered by this paucity of relevant data. More data on human reproductive effects of novel oncology drugs is urgently required to facilitate effective use of the growing array of oncofertility care options available., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Fertility preservation is a critical patient counseling component following cancer diagnosis. The aim of this study was to compare change and quality of fertility preservation information available to patients on the websites of National Cancer Institute (NCI)-designated cancer centers over 5 years (2015 to 2020) for both women and men., Methods: All NCI-designated cancer center websites were queried for information on oncofertility in 2020 publicly available to patients using the methodology and rubric previously employed in 2015. Data was evaluated based on each center's city, county, and state by demographic data obtained from the US Census. Additionally, the yearly number of in vitro fertilization (IVF) cycles performed in the city, county, and state of each NCICC was included using websites of clinics reporting data to the Society for Assisted Reproductive Technology., Results: Significantly NCICCs have a standalone pages for fertility preservation in 2020 compared with 2015 (p = 0.004). There is a statistically significant association between discussion of male fertility and the number of fertility centers in the county and state of the NCICC (p = 0.04 and p = 0.001). NCICCs in counties in the highest quartile of per capita income were significantly more likely to address male fertility (p = 0.03)., Conclusions: Oncofertility information on NCICC websites has improved between 2015 and 2020. The impact of cancer treatment on male fertility, while improved, is still limited, particularly in counties with lower per capita income., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To normalize age-dependent effects on standardized measures of spermatogonial quantity such as the number of spermatogonia per tubular cross-section (S/T) or fertility index., Design: Published quantitative histologic data on human spermatogonial numbers were used to create Z-scores for reference means and tested on archived testicular tissue samples., Setting: Retrospective cohort study., Patient(s): The sample cohort comprised testicular samples from 24 boys with cancer diagnosis and 10 with Klinefelter syndrome, as part of the fertility preservation programs NORDFERTIL and Androprotect, as well as archived histologic samples from 35 prepubertal boys with acute lymphoblastic leukemia and 20 testicular biobank samples., Intervention(s): None., Main Outcome Measure(s): Z-score values for S/T and fertility index on the basis of morphology and germ cell-specific markers (MAGEA4 and/or DDX4) were calculated, and the impact of cancer therapy exposure and genetic disorders on Z-score values was evaluated., Result(s): The Z-scores for S/T values in the nontreated samples (-2.08 ± 2.20, n = 28) and samples treated with nonalkylating agents (-1.90 ± 2.60, n = 25) were comparable within ±3 standard deviations of the reference mean value but differed significantly from samples exposed to alkylating agents (-12.14 ± 9.20, n = 22) and from patients with Klinefelter syndrome (-11.56 ± 4.89, n = 8). The Z-scores for S/T were correlated with increasing cumulative exposure to alkylating agents (r = -0.7020)., Conclusion(s): The Z-score values for S/T allow for the quantification of genetic and cancer treatment-related effects on testicular tissue stored for fertility preservation, facilitating their use for patient counseling., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Primum non nocere. As physicians, our goal is to treat illnesses and alleviate suffering; however, in doing so, we can generate new problems in a game of medical whack-a-mole. For some patients, certain consequences or side effects are tolerable, while others may believe they have no alternative. For a male patient with infertility, a thorough history is imperative to elucidate whether the patient has been or is currently being exposed to medications that will harm libido, spermatogenesis, ejaculation, or the hypothalamic-pituitary-testosterone axis. This article will review the most common medications causing iatrogenic male infertility as well as options to minimize or even reverse their impact., (Copyright © 2021. Published by Elsevier Inc.)

Cryopreservation of immature testicular tissue is an experimental strategy for the preservation of fertility in prepubertal boys that will be subjected to a gonadotoxic onset, as is the case of oncologic patients. Therefore, the objective of this study was to assess the impact of chemotherapeutic treatments on the testicular histologic phenotype in prepubertal patients. A total of 56 testicular tissue samples from pediatric patients between 0 and 16 years old (28 with at least one previous chemotherapeutic onset and 28 untreated controls) were histologically analyzed and age-matched compared. At least two 5-μm sections from testis per patient separated by a distance of 100 μm were immunostained for the germ cell marker VASA, the spermatogonial markers UTF1, PLZF, UCHL1, and SALL4, the marker for proliferative cells KI67, and the Sertoli cell marker SOX9. The percentage of tubule cross-sections positive for each marker and the number of positive cells per tubule cross-section were determined and association with the cumulative dose received of each chemotherapeutic drug was statistically assessed. Results indicated that alkylating agents, cyclophosphamide and ifosfamide, but also the antimetabolite cytarabine and asparaginase were associated with a decreased percentage of positive tubules and a lower number of positive cells per tubule for the analyzed markers. Our results provide new evidences of the potential of chemotherapeutic agents previously considered to have low gonadotoxic effects such as cytarabine and asparaginase to trigger a severe testicular phenotype, hampering the potential success of future fertility restoration in experimental programs of fertility preservation in prepubertal boys.

Background: Recent studies have shown that epigenetic alterations, such as those involving lysine-specific demethylase 1 (LSD1), lead to oncogenic activation and highlight such alterations as therapeutic targets. However, studies evaluating the effect of LSD1 inhibitors on male fertility are lacking., Objectives: We analyzed the potential toxicity of a new selective LSD1 inhibitor, N-[(1S)-3-[3-(trans-2-aminocyclopropyl)phenoxy]-1-(benzylcarbamoyl)propyl] benzamide (NCL1), in testes., Materials and Methods: Human testicular samples were immunohistochemically analyzed. Six-week-old male C57BL/6J mice were injected intraperitoneally with dimethyl sulfoxide vehicle (n = 15), or 1.0 (n = 15) or 3.0 (n = 15) mg/kg NCL1 biweekly. After five weeks, toxicity and gene expression were analyzed in testicular samples by ingenuity pathway analysis (IPA) using RNA sequence data and quantitative reverse transcriptase (qRT)-PCR; hormonal damage was analyzed in blood samples. NCL1 treated GC-1, TM3, and TM4 cell lines were analyzed by cell viability, chromatin immunoprecipitation, flow cytometry, and Western blot assays., Results: LSD1 was mainly expressed in human Sertoli and germ cells, with LSD1 levels significantly decreased in a progressive meiosis-dependent manner; germ cells showed similar expression patterns in normal spermatogenesis and early/late maturation arrest. Histological examination revealed significantly increased levels of abnormal seminiferous tubules in 3.0 mg/kg NCL1-treated mice compared to control, with increased cellular detachment, sloughing, vacuolization, eosinophilic changes, and TUNEL-positive cells. IPA and qRT-PCR revealed NCL1 treatment down-regulated LSD1 activity. NCL1 also reduced total serum testosterone levels. Western blots of mouse testicular samples revealed NCL1 induced a marked elevation in cleaved caspases 3, 7, and 8, and connexin 43 proteins. NCL1 treatment significantly reduced GC-1, but not TM3 and TM4, cell viability in a dose-dependent manner. In flow cytometry analysis, NCL1 induced apoptosis in GC-1 cells., Conclusions: High-dose NCL1 treatment targeting LSD1 caused dysfunctional spermatogenesis and induced caspase-dependent apoptosis. This suggests the LSD1 inhibitor may cause testicular toxicity via the regulation of apoptosis., (© 2020 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Testicular cancers are the most frequent and the most curable cancers in young men. Treatments of these cancers represent a great success with cure rate over to 95 %. However, chemotherapy side effects may occur during or after several years post-treatment. This review aimed to highlight complications and physical and psychological side effects occurring mainly after chemotherapy treatment for testicular cancer, and to propose a personalized post-cancer plan specific for patients treated for testicular cancer. Treatments of these cancers can cause short-term complications (asthenia, nausea, vomiting, alopecia..). These side effects disappear within a few months after the end of the treatments. Late complications may occur several years post-treatment. Cardiovascular disease, metabolic syndrome and secondary neoplasia represent the most severe late effects among patients treated for testicular cancer. Given the increased incidence of these chemotherapy-induced side effects, it is indispensable to establish a specific follow up which must include a particular vigilance on the risk of occurrence of second cancer, a follow-up of the cardio-vascular risk factors, pulmonary and auditory follow-up, and early detection of psychosocial disorders., (Copyright © 2019. Published by Elsevier Masson SAS.)

Chemotherapy treatment is a mainstay of anticancer regimens, significantly contributing to the recent increase in childhood cancer survival rates. Conventional cancer therapy targets not only malignant but also healthy cells resulting in side effects including infertility. For prepubertal boys, there are currently no fertility preservation strategies in use, although several potential methods are under investigation. Most of the current knowledge in relation to prepubertal gonadotoxicity has been deduced from adult studies; however, the prepubertal testis is relatively quiescent in comparison to the adult. This review provides an overview of research to date in humans and animals describing chemotherapy-induced prepubertal gonadotoxicity, focusing on direct gonadal damage. Testicular damage is dependent upon the agent, dosage, administration schedule and age/pubertal status at time of treatment. The chemotherapy agents investigated so far target the germ cell population activating apoptotic pathways and may also impair Sertoli cell function. Due to use of combined chemotherapy agents for patients, the impact of individual drugs is hard to define, however, use of in vivo and in vitro animal models can overcome this problem. Furthering our understanding of how chemotherapy agents target the prepubertal testis will provide clarity to patients on the gonadotoxicity of different drugs and aid in the development of cytoprotective agents.

Tyrosine kinase inhibitors (TKIs) are a targeted class of cancer therapies effective against a range of malignancies and their use is growing significantly each year. Many men taking TKIs desire children, yet very little is known about the potential for reproductive harm of these medications. The mechanism of action of TKIs suggest a possible route to impairment of sperm functional properties or spermatogenesis., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

This study investigates the ameliorative potential of Launea taraxacifolia (LT) aqueous leaf extract on cisplatin-induced testicular dysfunction in Wistar rats. Thirty rats were randomly divided into six groups (A-F) of 5 rats each: Group A which served as control received water; Group B was intraperitoneally (ip) injected 10 mg kg(-1) body wt cisplatin on day 21; Groups C and D were given 100 and 400 mg of LT via oral administration, respectively, for 21 days while Groups E and F received similar treatment as Groups C and D, respectively, and then exposed to ip administration of 10 mg kg(-1) body weight cisplatin on the 21st day. Exclusively, Cisplatin-exposed Group B rats showed reduced sperm characteristics and increased sperm morphological abnormalities; distorted histological architecture of seminiferous tubules; significantly increased lipid peroxidation (LPO) and decreased activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH)levels in the testes. These parameters in LT alone treated Groups C and D were not markedly different compared with the control group. The rats with the combined treatment in Groups E and F showed significantly improved sperm parameters, testicular histo-architecture and antioxidant enzymatic activities. Conclusively, aqueous extract of L. taraxacifolia has protective potential against cisplatin damage., (© 2014 Blackwell Verlag GmbH.)

Increasing numbers of men are having or wanting children after chemotherapy treatment. This can be attributed to improvements in cancer therapies that increase survival. However, a side effect of most chemotherapy drugs is disruption of spermatogenesis and a drastic reduction in sperm count and quality. Although many men eventually recover reproductive function, as indicated by normal semen analyses, there is no clinical test that can assess sperm quality at a high level of sensitivity. Sperm fluorescent in situ hybridization (i.e., FISH) and several different tests for deoxyribonucleic acid (DNA) fragmentation have been used infrequently in clinical assessment. Animal models of chemotherapy-induced testicular damage are currently being used to identify potential molecular biomarkers that may be translatable to humans-these include sperm messenger RNAs, microRNAs, histone modifications, and DNA methylation patterns. Changes in these molecular measurements are quantitative and sensitive, potentially making them important clinical biomarkers of testicular function after chemotherapy treatment., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

No clear clinical guidelines exist on how to counsel male cancer patients about fertility preservation. Detailed counseling is recommended before treatment when issues of collection and storage need to be highlighted. Concern about the quality of sperm collected before and/or after treatment in terms of assisted reproduction is needed, and the potential outcomes should be discussed early as part of cancer survivorship. The discussion should be sensitive and tailored to the ethical situation based on the age of the patient, the severity of the illness, the need to initiate treatment, and genetic risk. Cryopreservation should be attempted/achieved before cancer treatment is initiated. Cryopreservation should not be performed during treatment or for some time after treatment because of the chromosomal and structural damage to sperm from cancer treatment. Contraception should be instigated during this period., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Cancer treatments are detrimental to spermatogenesis. This series reviews effects of anticancer therapies on male fertility, current and future approaches to determine sperm health, and gives recommendations for patient management., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Fertility-related concerns are frequently encountered in the course of providing care to oncologic patients. Male cancer survivors who desire paternity after cancer treatment face the question of whether their posttherapy sperm can be safely used in either natural or assisted conception attempts. Although the reproductive risks of using sperm genetically compromised by chemotherapy or radiotherapy include impaired embryonal development, pregnancy loss, and congenital anomalies in offspring, there is a general lack of consensus in the literature concerning the persistence of sustained genotoxic effects, making it difficult to assuredly quantify the level of risk involved. Transmission of chemotherapeutic agents via seminal plasma is another potential risk that has not yet been well evaluated. Sperm chromosomal aneuploidy rates and DNA fragmentation indices provide means of assessing genomic damage that could prove useful in genetic counseling efforts. Ultimately, additional research is needed to clarify investigational discrepancies and establish a stronger body of evidence that would allow for the development of clinical guidelines to assist cancer patients considering posttreatment conception in their decision-making processes., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer.

Objective: To assess the effects of taxane-based chemotherapy on the male reproductive axis, and, therefore, its impact on spermatogenesis and fertility., Design: Controlled clinical study., Setting: Patients with cancer in an academic research environment., Patient(s): Forty male patients of reproductive age with cancer with solid tumor at diagnosis, who had been scheduled to receive taxane-based chemotherapy., Intervention(s): The patients were given treatment with docetaxel or paclitaxel combined with gemcitabine or carboplatin. Blood sampling and testicular ultrasonography were performed before and after completion of chemotherapy., Main Outcome Measure(s): In all patients, serum levels of inhibin B, FSH, and LH were measured, and, in half of the patients, bilateral testicular volume was also measured., Result(s): There was a statistically significant decrease in serum inhibin B and increase in serum FSH in all patients after the completion of the taxane-based chemotherapy. The median LH levels did not exhibit a statistically significant increase after the last cycle. Bilateral testicular volume exhibited a statistically significant decrease in 19 out of 20 patients (95%) after completion of chemotherapy., Conclusion(s): Taxane-based chemotherapy induces the reduction of inhibin B and the reciprocal elevation of FSH, which are associated with significant gonadal damage in the early stages after completion of chemotherapy., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Preserved fertility is an important issue for testicular cancer (TC) survivors., Objective: Our aim was to examine any difference regarding paternity and testicular function following two, three, or four cycles of cisplatin-based chemotherapy for TC., Design, Setting, and Participants: A national multicentre follow-up survey assessing morbidity among survivors of unilateral TC diagnosed from 1980 to 1994 was conducted during the period 1998 to 2002. Of the 1814 men invited, 1462 (80.6%) participated by responding to a mailed questionnaire and/or undergoing a clinical examination including laboratory assessments. The present study includes the 316 participants up to 65 yr of age treated with two to four cycles of standard cisplatin-based chemotherapy without additional treatment beyond surgery., Measurements: Self-reported paternity following treatment for TC according to number of cycles was assessed among men who reported antegrade ejaculation and attempts at posttreatment conception (n=106). Kaplan-Meier analysis, log-rank test, and Cox regression were applied. Gonadal hormones (n=305-314) and sperm counts (n=71) by number of cycles were assessed by linear by linear association or Mann-Whitney tests., Results and Limitations: At median 12-yr follow-up, 80% (85 of 106) had succeeded in their attempts of achieving posttreatment paternity (two cycles: 100%; three: 83%; four: 76%; p=0.022). For all patients the 15-yr actuarial paternity rate was 85%. The association between posttreatment paternity and number of cycles remained significant in the multivariate analysis (p=0.032). High serum follicle-stimulating hormone values were more common with increasing number of cycles (p=0.037), but there were no differences in serum luteinising hormone, serum testosterone, or sperm counts. Few men treated with two cycles and a limited number of sperm samples are the main limitations of this study., Conclusions: The prospects of future paternity after two to four cycles of cisplatin-based chemotherapy are good, and our data suggest that the prospects improve with decreasing number of cycles., (Copyright 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

With the advent of the modern cancer treatment, survival rates have improved substantially raising new concerns towards quality of life issues such as future fertility and offspring welfare. Cancer researchers are expanding their focus beyond survival and recurrence rates to include maximization of fertility potential for young cancer patients. Despite promising cure rates with chemotherapy, studies have shown it to act as a double edge sword by adversely affecting male fertility. Chemotherapeutic agents act by hindering rapidly proliferating cells, hence exerting their gonadotoxic effect. The extent of damage to germ cells and eventual fecundity depends on the class of chemotherapeutic agent, dosage, spermatogenetic stage targeted as well as the original pretreatment fertility potential of the patient. In this review, we provide a contemporary overview of the effects of anticancer agents on male fertility. Gonadotoxicity caused by these agents will be analyzed followed by the contemporary measures to preserve future fertility. Both established and potential strategies of fertility preservation will be discussed with emphasis on cryopreservation and its efficacy in conjunction with assisted reproductive technologies in addition to the current recommendations for this preservation modality. Finally, contemporary research on the welfare of offspring of cancer survivors will be reviewed.

To assess sperm cryopreservation among males newly diagnosed with cancer aged 13 years and older, attending oncologists assigned infertility risk (yes/no) to patients and reported whether their patients engaged in sperm cryopreservation. Only 28.1% of informed at-risk patients banked sperm. Utilization of sperm banking was significantly associated with a diagnosis of central nervous system (CNS) malignancy or non-CNS solid tumor diagnosis, higher socioeconomic status, and not being a member of an Evangelical religious group. These results suggest that sperm banking is underutilized among adolescent males newly diagnosed with cancer, and that strategies to increase the engagement in this fertility preservation method are needed.

Purpose: To analyze fertility in male patients treated with various combinations of radiotherapy and chemotherapy, with or without alkylating agents, or with radiotherapy alone for Hodgkin's lymphoma., Patients and Methods: Follicle-stimulating hormone (FSH) levels were measured in patients with early-stage upper-diaphragmatic disease enrolled in four European Organisation for Research and Treatment of Cancer (EORTC) trials (H6-H9). Median follow-up after therapy was 32 months. Patients with FSH measurement at least 12 months after end of treatment (n = 355) were selected to assess post-treatment fertility. Patients with FSH measurement 0 to 9 months after therapy (n = 349) were selected to analyze fertility recovery; of these, patients with elevated FSH (> 10 U/L; n = 101) were followed until recovery. Factors predictive for therapy-related infertility were assessed by logistic regression., Results: The proportion of elevated FSH was 3% and 8% in patients treated with radiotherapy only or with nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], epirubicin, bleomycin, vinblastine, prednisone [EBVP]); it was 60% (P < .001) after chemotherapy containing alkylating agents (mechlorethamine, vincristine, procarbazine, prednisone [MOPP], MOPP/doxorubicin, bleomycin, vinblastine [ABV], bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone [BEACOPP]). After a median time of 19 months, recovery of fertility occurred in 82% of patients treated without alkylating chemotherapy. This proportion was 30%, statistically (P < .001) lower in those treated with alkylating chemotherapy, and median time to recovery was 27 months. The post-treatment proportion of elevated FSH increased significantly (P < .001) with the dose of alkylating chemotherapy administered, and recovery was less frequent and slower after higher doses. Age more than 50 years and stage II disease also contributed to poor outcome., Conclusion: Fertility can be secured after nonalkylating chemotherapy for Hodgkin's lymphoma. In contrast, alkylating chemotherapy has a dismal effect, even after a limited number of cycles.

Decreased secretion of pituitary gonadotropins, by decreasing gonadal function, may possibly protect against the sterilizing effects of chemotherapy. Although previous claims that primordial germ cells fare better than germ cells that are part of an active cell cycle have been made, this hypothesis has not been seriously tested clinically until recently. The only prospective randomized study performed to date found that gonadotropin releasing hormone agonistic analogue (GnRH-a) protected the ovary against cyclophosphamide-induced damage in Rhesus monkeys by significantly decreasing the number of follicles lost during the chemotherapeutic insult. We have administered a monthly depot i.m. injection of GnRH-a to more than 125 young patients exposed to gonadotoxic chemotherapy for malignant or nonmalignant diseases, after informed consent, starting before chemotherapy for up to 6 months, in parallel and until the end of chemotherapeutic treatment. Less than 7% developed irreversible hypergonadotropic amenorrhea. The remainder (>93%) resumed cyclic ovarian function, of which 32 patients spontaneously conceived 46 times. These patients were compared to a control group of over 125 patients of comparable age (15-40 years), who were similarly treated with chemotherapy but without the GnRH-a adjuvant. The 2 groups were similar in age, diagnosis, and the ratio of HD to non-Hodgkin lymphoma patients. The 2 groups also received similar doses of radiotherapy exposure and the proportion of radio-plus chemotherapy-treated patients was similar. The cumulative doses of each chemotherapeutic agent and the mean or median radiotherapy exposure did not differ between the groups. Our and others' results support the effectiveness of GnRH-a administration also to patients receiving cyclophosphamide pulses for systemic lupus erythematosus and other autoimmune diseases. Possible explanations for the beneficial effect of the GnRH-a on minimizing the gonadotoxic effect of chemotherapy are discussed. Multi-center prospective, randomized studies are awaited to substantiate the in vivo effect of GnRH-a as an unequivocal means of minimizing follicular apoptosis.

The dermatologist employs systemic agents with likely gametotoxic side effects, including cytotoxic, immunosuppressive, immunomodulatory and biological agents. The impact of chemotherapy on male fertility depends on the treatment protocol as well as the pre-treatment spermatogenesis status. Sperm concentration starts to drop about 2 weeks after beginning chemotherapy and reaches a maximum after 2-3 months. About half show recovery after 12-36 months. One year after therapy is completed, a treated patient has no increased risk of fathering a malformed child. There are no reports of methotrexate patients fathering children with malformations, most likely because impaired fertility or embryogenesis arrest. Cryopreservation of male gametes should be recommended prior to cytotoxic treatment, since the likelihood of post-treatment fertility is unpredictable. The cryopreservation causes a loss of vital spermatozoa by 30-70% but does not influence the genetic information of gametes. Males treated with retinoids have no reproductive safety risk. Biologicals inhibiting TNF alpha show a positive effect on sperm function in vitro.

The impressive increase in the survival rate of childhood cancer patients has produced increased interest in quality of life issues. This research addresses nurse practice issues in determining whether the newly diagnosed adolescent male patient is offered the option of sperm banking before undergoing chemotherapy treatment. Questionnaires were distributed to nurses and nurse practitioners on 3 inpatient and outpatient units who care for adolescent male cancer patients at the time of diagnosis, during chemotherapy, and during follow-up care. Findings indicate that 96.3% of respondents agreed that all male patients undergoing cancer treatment with infertility as a potential side effect should be offered sperm banking. Respondents viewed oncologists and nurse practitioners as appropriate professionals to discuss the option. Lack of knowledge regarding sperm banking could be limiting nurses' willingness to introduce the topic, and education regarding cryopreservation may improve their knowledge and practice.

The survival rate of children and adolescents with cancer has improved dramatically in the last decades so that the prospect of survival in adulthood is today a realistic expectation for about 70% of the treated patients. However, the deleterious impact that chemotherapy and radiotherapy have on the reproductive function and future fertility could compromise the quality of life of the survivors in adulthood. The interest of the scientific community on this topic is increasing and focused on a more accurate evaluation of the reproductive risk among cancer treated children and on the development of less aggressive therapies. In the present review, some information about the long-term effects on the male reproductive function, particularly vulnerable to the cancer therapies, are reported from clinical and experimental studies. Furthermore, the concern about the development of pharmacological treatments and assisted reproductive techniques that might preserve or restore the fertility potential in children being treated with gonadotoxic cancer therapy, is discussed. These new strategies are still under experimentation and deeper knowledges on the functional development of the gonads during infancy, both in human and animals models are required. On the other hand, the future clinical application of these strategies in children rise important ethical and legal problems.

Objective: To assess Sertoli cell involvement in postchemotherapy azoospermia., Design: Case report., Setting: Teaching hospital., Patient(s): A 31-year-old azoospermic man who underwent cancer cytotoxic chemotherapy for non-Hodgkin's lymphoma at 13 years of age., Intervention(s): Testicular biopsy specimens were obtained for sperm recovery in preparation for intracytoplasmic sperm injection. The biopsy specimens were evaluated by quantitative immunohistochemistry for the immature Sertoli cell markers cytokeratin 18 (CK-18) and D2-40., Main Outcome Measure(s): Extent of immature Sertoli cells., Result(s): A fraction of Sertoli cells (13%) in the atrophic tubules of this patient reexpressed the intermediate filament protein CK-18, which is normally absent after puberty, but not the D2-40 antigen, an Mr 40,000 a-linked membrane glycoprotein, whose loss of expression at puberty marks an irreversible step in Sertoli cell maturation. Tubules with normal spermatogenic progression lined by Sertoli cells negative for CK-18 were also observed., Conclusion(s): A fraction of Sertoli cells of this patient initially progressed to full maturation at puberty and reverted to a dedifferentiated state marked by reexpression of CK-18 as a consequence of chemotherapy. This inactivation of Sertoli cells caused by the cytotoxicity of the chemotherapeutic drugs may have contributed to the spermatogenic impairment and resulting infertility.

Improvements in cancer survival raise infertility issues in young patients suffering from malignancies. The aim of the study is to review current knowledge on the effect of chemotherapy (CT) and radiotherapy (RT) for testis and hematological neoplasms on testicular function. Cisplatin-based regimens for testis neoplasm induce temporary azoospermia; permanent damage can occur with high doses (400-600 mg/m(2)). Alkylating agents are very effective for hematological neoplasm therapy but extremely dangerous to germinal epithelium. Damage can be irreversible. Spermatozoa cannot tolerate irradiation doses higher than 6 Gy. Leydig cells are damaged by doses higher than 15 Gy. A-Spermatogonia have been shown to survive after CT and RT and their recovery for post-treatment graft has been recently developed in animal models. Infertility counselling before treatment in young oncological patients is mandatory. Cryopreservation is the best option for fertility protection.

The improvement in life expectancy, following better cancer therapy combined with new options in treating male infertility have increased the use of sperm freezing. We describe a rare case of twin pregnancy of a childless widow, using donated oocytes after ICSI with her deceased husband's banked frozen spermatozoa. Sperm was frozen before chemotherapy treatment and a written consent for future thawing and injection to donor oocytes was given. Use of thawed spermatozoa after death was not mentioned in the consent form. During the husband's illness years, ICSI of donated oocytes fertilized with thawed spermatozoa yielded three embryos, but no pregnancy was achieved after ET. While waiting for a subsequent oocyte donation, the male partner died of his malignancy. The woman expressed her wish to be treated with the frozen spermatozoa of her deceased husband. Since the original informed consent did not cover postmortem use of the husband's sperm, a special application for its use was made and subsequently approved by the Israeli Ministry of Health legal advisor. Another six donated oocytes were fertilized with the deceased's thawed spermatozoa, and the transfer of four embryos to the uterine cavity resulted in a twin pregnancy and later delivery of two healthy babies. This case emphasizes the importance of written informed consent signed by patients with a life-threatening disease at the time of banking spermatozoa, and discussing the possibility of its posthumous use. Several legal and ethical concerns are discussed.

Cancer treatments are well known to adversely affect male fertility. Reduction of sperm output arises from the cytotoxic effects of chemo- or radiotherapy upon the spermatogenic epithelium. However, if the epithelium survives there is a hazard to reproduction as the treatments are also mutagenic. The presence of DNA damage in the male genome is shown in animal experiments where there is transgenerational expression as a variety of effects ranging from miscarriage to carcinogenesis. The application of DNA damage methodology to sperm provides the opportunity for direct assessment. The Comet and Chromatin structure assays (SCSA) measure DNA damage by different principles, however, conclusions arising from the data are similar. DNA damage is present in sperm from fertile and infertile men and there is some association with infertility. Both assays detect sperm DNA damage after in vivo treatment with genotoxic agents. In a man treated with chemotherapy for cancer there was increased and persistent DNA damage in sperm. This information is consistent with the generation of human genetic diseases after conception with sperm carrying high loads of DNA damage. Whilst studies have not supported any association between paternal cytotoxic cancer therapy and genetic disease in their children, it would be unwise to discount these observations. The institution of better surveillance of genetic disease in the offspring of men surviving cytotoxic therapies may provide more robust risk assessment.

Testicular tumors and malignant lymphomas are, with increasing incidence, the most frequent malignant diseases in men between the age of 15 and 34. With the introduction of cisplatin-based polychemotherapy, cure rates rose to over 90% in patients with germ cell tumors and were comparably favorable at around 80% in those with malignant lymphomas. In view of these high cure rates, increasing clinical importance is attached to chemotherapy induced fertility disorders. One problem involved in assessing the influence of chemotherapy on fertility is the fact that the malignant disease itself strongly alters spermatogenesis. This complicates an evaluation of the effect of cytostatic therapy on fertility disorders. There are significant cytostatic- and dose-specific differences. Longterm infertility due to cytostatic therapy may be expected in more than 50% of the patients at a cumulative dose of cisplatin > 0.6 g/m(2), cyclophosphamide > 6 g/m(2), and procarbazine >/= 4 g/m(2). However, it takes up to 3 years or more for spermatogenesis to recover after the termination of chemotherapy. An individual assessment of the post-therapeutic fertility status is extremely limited, since variance of the pretherapeutic fertility status causes interindividual differences, and the numerical data mentioned above only permit a vague estimation. Before patients undergo cytostatic therapy, cryopreservation of germ cells should thus be suggested or, in some cases, testicular extraction of spermatozoa., (Copyright 2001 S. Karger GmbH, Freiburg)

Because the primary aim of adjuvant therapy for melanoma is not curative, all the possible aspects of quality of life have to be considered. One aspect of increasing importance is fertility. The effect of adjuvant interferon alpha-therapy for malignant melanoma on male fertility has not been systematically investigated. In the present study, twelve male patients with primary cutaneous melanoma (pT3, 4; N0; M0) who were taking adjuvant low-dose interferon alpha2b (3 x 3 mio U/week) for one year were included. Inhibin B--an established marker of male fertility-was measured with an immunosorbent assay before and after one year of interferon alpha-therapy to investigate whether this treatment has any influence on fertility. The results were compared with those from normal controls (n=40). The mean serum inhibin B concentration in melanoma patients before interferon therapy was 225.4 +/- 112.5 pg/mL; after treatment the level was 229.6 +/- 82.0 pg/mL. This difference was not statistically significant (p>0.05). The serum inhibin B concentration in controls was 201.5 +/- 17.1 pg/mL, which was not statistically different from either untreated or interferon-treated melanoma patients (p>0.05). We conclude that low-dose interferon alpha does not have a significant (negative) effect on inhibin B or male fertility.

With the advancement of medical science, most cancers in children are now treatable, the cure rate being almost 85%. In boys, one side effect of treatment (chemotherapy and radiotherapy) is destruction of the sperm precursor cells in the testis, resulting in the failure of sperm formation after puberty, and consequent infertility. At the time of anti-cancer treatment, future fertility of the boy patient is at the very bottom of the relative quality of life (RQL) parameters list; however, in adults infertility is an important issue following cure from cancer. In this article we have first reviewed the existing situation with regard to the state of the art of fertility preservation in young boys with cancer, and have then raised clinical and ethical issues and suggested a way forward. The review concludes with the emphasis that certain important issues still need to be resolved and, until these are, then the different techniques available should be confined to approved, ethical clinical trials where efficacy and safety can be fully evaluated.

Cytotoxic therapy is effective in treating various cancers, but many of the agents used can cause sterility in men, regardless of the age at which they were treated. Originally, it was thought that infertility in individuals who had undergone cytotoxic therapy resulted from the destruction of stem spermatogonia. However, studies using rats suggest that some stem spermatogonia can survive cytotoxic therapy and that infertility is caused by the inability of these spermatogonia to differentiate. The author believes that the failure of these cells to differentiate may be related to the high levels of intratesticular testosterone encountered in these situations. In rats that have previously received cytotoxic therapy, the administration of a gonadotrophin-releasing hormone (GnRH) agonist restores the ability of spermatogonia to differentiate, and as a result normal spermatogenesis returns. This finding suggests that GnRH agonists show promise as a treatment for male sterility induced by cytotoxic therapy, although further studies are required.

In the past twenty years, combined therapeutic regimens have improved the survival rare in many human tumors. Chemotherapy plays a significant role on this outcome. Unfortunately, many chemotherapeutic agents have adverse effects on gonadal function. The Authors examine the pathophysiology of gonadal damage in male diagnosed with cancer and treated with chemotherapeutic agents. Infertility and/or impotence can occur on these patients: the relationships between chemotherapy and tumors, towards seminal and sexual dysfunctions, are focused. Moreover, current possibilities to preserve recovery both fertility and sexual functions and discussed.

A study of fertility was conducted in postpubertal male patients who had been treated for acute lymphoblastic leukemia (ALL) during childhood or adolescence between 1970 and 1980. Thirteen men (age 18 to 35 years) participated on a volunteer basis. Their age at diagnosis was between 2 and 15 years. Therapy followed the protocol "Memphis VII (Pinkel)." Interview, physical examination, andrological studies (ejaculate), and hormone status (luteinizing hormone, follicle-stimulating hormone, and testosterone) were performed at least 5 years after completion of therapy. No normozoospermia was achieved; 10 patients were identified with asthenozoospermia and 3 patients with azoospermia. With respect to these data, patients treated for ALL between 1970 and 1980 have more significantly impaired spermatogenesis than expected.

Previous studies have shown that treatment of rats with gonadotropin-releasing hormone (GnRH) analogues or steroids either before exposure to procarbazine or radiation or after irradiation enhances subsequent levels of spermatogenesis. We demonstrate here that giving a GnRH agonist after procarbazine injection also enhances spermatogenesis and fertility. We also demonstrate that GnRH agonist stimulated recovery of spermatogenesis and fertility not only when the hormone was administered immediately after irradiation, but also at 20 weeks after irradiation, after the decline in spermatogenesis had occurred. These results suggest that GnRH agonist treatment given to azoospermic men after cytotoxic therapy for cancer may stimulate the recovery of spermatogenesis and fertility.

The improved survival in recent years of young males suffering from cancer, and an understanding of the gonadotoxic effects of chemotherapy treatment, have motivated patients and clinicians to preserve fertility potential before embarking on adjuvant therapy. Among 231 men (mean age 28.0; range 15-56 years) diagnosed with malignant disease and referred to our unit for semen cryopreservation, 112 patients (49.8%) had reduced sperm quality of <10 x 10(6) motile spermatozoa per ejaculate; however, most had sufficient suitable spermatozoa for freezing. In 40 patients (17.3 %) the semen samples were not frozen because of complete azoospermia (n = 32) or only immotile sperm in the ejaculate (n = 2), while six men were unable to produce a single sample. Some 79 men had testicular tumours (group I), 121 suffered from haematological malignancy (leukaemia or lymphoma; group II), and 27 had cancer of different causes (group III). Men in group I had significantly lower (P < 0.001) sperm quality compared with groups II and III. There was no difference between patients with seminoma and non-seminoma tumours. In the haematological malignancy group there was no difference in sperm parameters between leukaemia (n = 12) and lymphoma (n = 77) patients, but patients with Hodgkin's lymphoma had significantly lower sperm quality compared with non-Hodgkin's lymphoma. Following chemotherapy, six couples attended the clinic for assisted conception treatment using the frozen semen. Two had successful intrauterine insemination cycles which each resulted in delivery of a healthy girl; one couple had conceived in their first in-vitro fertilization (IVF) attempt, followed by delivery of healthy twins. Two women conceived after intracytoplasmic sperm injection treatment and the sixth woman achieved only biochemical pregnancy after numerous IVF and frozen embryo replacement cycles. We recommend that a properly designed programme for semen cryopreservation for cancer patients should be developed in leading tertiary assisted conception centres, which have adequate facilities and experience for cryopreservation and can offer the whole range of appropriate assisted reproductive treatment and counselling.

Objective: To investigate the impact of cytostatic chemotherapy on long-term fertility in patients with testicular germ cell cancer., Background: Many patients with testicular germ cell cancer show impaired spermatogenesis before undergoing cytotoxic chemotherapy. The known infertility before treatment and the reversibility of the fertility problems observed in some of them after successful anticancer treatment so far have prevented an assessment of the true impact of chemotherapy on long-term fertility. The introduction of a wait-and-see strategy (surveillance) for patients with testicular cancer and recent prospective trials comparing patients with and without cytotoxic chemotherapy now have provided the means for estimating the extent to which chemotherapy itself affects long-term fertility., Result(s): Whether spermatogenesis is impaired irreversibly by chemotherapy is determined by the cumulative dose of cisplatin. At cumulative doses > 400 mg/m2, irreversible impairment of gonadal function should be expected., Conclusion(s): At cumulative cisplatin doses < 400 mg (equivalent to 4 courses of state-of-the-art treatment), chemotherapy is unlikely to cause irreversible damage to fertility.

To assess the testicular toxicity induced by compound C, a new platinum complex being developed as an anti-cancer drug, the substance was intravenously administered to male rats at doses of 1, 3 and 10 mg/kg/day for 4 weeks and at doses of 0.3, 1 and 3 mg/kg/day for 9 weeks. Males were cohabited with non-treated females after these treatment periods and at sacrifice the genital organ weights and number of sperm in the testis were recorded and a histopathological examination performed. The females were sacrificed on day 13 of gestation and the numbers of corpora lutea, implantations and resorptions were counted. In the 4 weeks treatment 10 mg/kg/day group, the testis weight increased while the weights of the epididymides, seminal vesicles and prostate decreased significantly, and the number of sperm was significantly decreased. Extension of seminiferous tubules, vacuolization of spermatocytes, spermatids and Sertoli cells, and degeneration of spermatocytes and spermatids were observed by histopathological examination. Copulation and impregnation were not affected by treatment but the implantation rate was significantly decreased in the 10 mg/kg/day group. These results show that compound C has testicular toxicity like other platinum complexes and that organ weight, number of sperm, number of implantation and histopathological examination are useful for detection purposes. Treatment with compound C for 9 weeks did not affect male reproductive function in spite of severe general toxicity. This suggests that testicular toxicity should be detected after 4 weeks rather than 9 weeks treatment.

Cytotoxic agents used in various therapies (anticancer treatments in particular) are known to be very deleterious to male fertility. In these situations, both quantitative (oligo and azoospermia) and qualitative alterations of the male reproductive system occur. What are the various possibilities to protect male reproduction? Sperm cryo-storage, prior to the beginning of chemotherapy and/or radiotherapy, is one possibility. However this possibility can only be offered to a relatively limited number of patients, due to the fact that the disease itself often causes gonadal abnormalities. Another possibility is the substitution of the most cytotoxic drugs by less deleterious agents, as well as, the reduction of the doses used in the therapeutic regimens. Progress in this field however remains very slow. Therefore, the use of various protective agents appears to be necessary. Of all the agents so far tested (anti-oxidants, GnRH analogs, FSH, steroids), the combination of medroxyprogesterone acetate and testosterone (MPA+T) is the one which has been the most studied both in men (contraception) and in rodents (contraception and protection). From a series of experiments using MPA+T in male rats, it appears that both qualitative and quantitative protection of fertility can be achieved against chemo- and radiotherapy. Progress in this field should be the prelude of clinical trials. This transfer from animals to men, should result as one of the activities of a pluri-disciplinary group supported by INSERM and entitled "Prosperm". The dialogue established in this group between researchers and physicians offers new perspectives in the domain of protection of spermatogenesis, at a time when this is most needed.(ABSTRACT TRUNCATED AT 250 WORDS)

In animal models the possibility has been explored that pharmacological inhibition of cell division in the spermatogenic epithelium during cytotoxic treatment for cancer would preserve fertility. Recent animal models are reviewed. In the rat, gonadotrophin releasing hormone (GnRH) analogues or a combination of a progestogen and an androgen will protect spermatogenesis from the cytotoxic and mutagenic effects of procarbazine and radiation. Cyclophosphamide toxicity is not alleviated by GnRH treatment. In the mouse, a GnRH analogue was ineffective against cisplatin testicular toxicity. Complete suppression of the spermatogenic process does not seem to be important for a successful outcome. These experiments serve to illustrate the inconsistency between different laboratories. However, it is argued that once the correct pharmacological approach and the mechanisms have been established in animal models, only then will it be possible to predict the efficacy of these adjuvant treatments to preserve fertility in men being treated for cancer.

Germinal cells are particularly sensitive to cancer chemotherapy in males. This toxicity is difficult to evaluate. It is the most frequently observed in young patients treated for curable cancers, by alkylants, specially if the treatment is intense and long. Depending on the patient and his age, on the cancer and its treatment, recovery of a normal spermatogenesis may be observed in a minority of cases and sometimes lately. This hazard must be told to the patient who is invited to preserve his sperm which is not always of enough good quality. There is no proved means to protect gonadal function. Therefore modifications of chemotherapy are desirable to decrease its toxicity.