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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 3
| Issue : 1 | Page : 13-17 |
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Oncofertility in males: A literature review
N Ashwini, Lohith Chengappa Appaneravanda, Devika Gunasheela
Department of Reproductive Medicine, Gunasheela Surgical and Maternity Hospital, Bengaluru, Karnataka, India
| Date of Submission | 30-Dec-2020 |
| Date of Acceptance | 31-Dec-2020 |
| Date of Web Publication | 30-Jan-2021 |
Correspondence Address:
Dr. N Ashwini
Gunasheela Surgical and Maternity Hospital, No. 1, Dewan N Madhava Rao Road, Basavanagudi, Bengaluru - 560 004, Karnataka
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/tofj.tofj_9_20
The aim of this study was to evaluate current literature on oncofertility specifically in males. We convey that malignancies on its own result in compromising semen quality in males, subsequently causing infertility or impaired fertility. Testicular cancer and Hodgkin's disease are aggressive in causing infertility compared to other malignancies. This review also aims to address the gonadotoxic nature of cancer therapy, outlining the cytotoxicity of radio and chemotherapy. We also address techniques that major fertility centers utilize for fertility preservation in males, specifically semen cryopreservation. Prepubertal males with malignancies are also assumed early care in fertility protection, experimental techniques such as spermatogonial stem cells preservation, and testicular tissue freezing has quickly become prevalent in giving patients hope of parenthood. Finally, we discuss some current oncofertility guidelines to care for male patients with cancers. We also evaluate the ethical constrains of semen cryopreservation and overall providing oncofertility care.
Keywords: Cryopreservation, gonodotoxic, malignancy, prepubertal males
How to cite this article:
Ashwini N, Appaneravanda LC, Gunasheela D. Oncofertility in males: A literature review. Onco Fertil J 2020;3:13-7 |
| Introduction | |  |
In India, the projected number of cancer patients for the year 2020 is 13 lakhs as per the national cancer registry, with an estimated 12% raise by 2025.[1],[2] Forty-three percent of cancers in men comprise prostate, lung, and colorectal cancers.[1],[3] The rate of new cases of cancer is 442.4/1 lakh men per year.[4] The most common cancers diagnosed in the reproductive age (15–45) are leukemia, bone, testicular cancer, and Hodgkin's lymphoma.[5] As a result of treatment innovations, the survival rates of young people with cancer have increased substantially. With 65% overall survival rates of young cancer patients treated with radiation and chemotherapeutic agents, the prevalence of long-term survivors in young adult population has been estimated to be 1 in 1000.[6],[7] It has been well established that male reproductive potential is compromised because of cancer treatment such as chemo/radiotherapy.[8],[9] Precision medicine is helping move cancer treatment from one-size-fits-all model to a more specific cancer therapy based on the detailed evaluation of the cancer subtype.[10] These advancements in cancer treatments have given a chance for a good percentage of patients suffering from malignancies to consider parenthood as an option through fertility preservation.[11]
This review aims to better understand the effects of cancer and cancer treatment on male fertility and also sheds light on current oncofertility recommendations. A review of recent literature has been carried out with an extensive literature search carried out on EMBASE, Scopus, and MEDLINE.
| Effect of Malignancies on Male Fertility | | |
Spermatogenesis and overall semen quality decline in the presence of malignancies as reported by multiple studies.[9],[12] However, certain types of cancers are more detrimental to sperm health than other types. Sex hormones in males are downregulated in cancer patients due to stress. Endocrine environment of tumor site causes alterations to the reproductive hormone activity.[9],[13] Tumors release cytokines which affect sperm motility. In certain cancers such as leukemia, lymphoma, and neurological cancers, the hypothalamic pituitary gonadal axis might be directly impaired by the invasion of tumor cells.[9],[14] A number of studies report that malignancies might cause malnutrition in patients, causing deficiency in key vitamins, minerals, and trace elements that is needed for optimal gonadal function.[9],[15] Cancers such as Hodgkin's lymphoma are associated with periodic spikes in fever (B-symptoms). Hyperthermia elevates scrotal temperatures causing damage to germinal epithelium, thus decreasing spermatogenic functions.[16],[17],[18] Several studies have indicated that histological modifications such as dysgenesis syndrome (25.2%), fibrosis of the seminiferous tubules (24%–60%), sertoli cell only syndrome (8%), and in situ carcinoma (5%–8%) are evident in the contralateral testis in patients with testicular cancer.[19],[20] Impairment of spermatogenesis in cancer patients with testicular cancer is multifactorial and may be related to (i) hormonal aberration (increased follicle-stimulating hormone, b-human chorionic gonadotrophin, a-fetoprotein, estradiol, and luteinizing hormone and decreased inhibin B and testosterone); (ii) a history of cryptorchidism, which seems to present more frequently in males with testicular cancer (Van Casteren NJ et al., 2008); and (iii) general dysfunction due to cancer itself (increased catabolic rate and malnutrition).[20],[21]
| Impact of Oncology Therapy on Male Fertility | | |
Radiotherapy
The testicular cells, especially the fast dividing sperm cells, are extremely sensitive to irradiation. The potential to recovery depends not only on the dose of radiation and dose per fraction but also the survival of spermatogonial population within the testis.[22] Low cytotoxic doses do destroy the pool of differentiating spermatogonia but are likely to result in only a temporary cessation in spermatogenesis. If the radiation dose is high, the spermatogonial stem cell (SSCs) number is drastically decreased and recovery may take many years.[22] With doses of more than 4 Gy, all the SSCs are depleted rendering the patient permanently sterile.[9],[23]
Radiotherapy relies on ionization of the atoms and molecules in the cell which causes the disruption of DNA integrity.[24],[25] This will consecutively disrupt the cell cycle causing apoptosis of cells. Radiotherapy is widely used in oncological care, as malignant cells do not have the potential to repair after radio exposure like healthy cells. Like cancer cells, germ cells are prone to similar effects.[9],[23],[24] The Leydig cells are more resistant to irradiation and dose of more than 20 Gy is needed to produce hypogonadism. Testicular irradiation used to treat carcinoma of testis is associated with high rate of permanent sterility.[24],[25] Vascular disease induced by pelvic radiation can reduce blood flow in the pelvic and penile vessels causing erectile dysfunction as a long-term complication.[26]
Chemotherapy
In humans, the testis is more sensitive to chemotherapy than the ovary [Table 1].[9],[23] Gonadotoxicity of the testis affects spermatogenesis more than testosterone production, as the germinal epithelium is extremely vulnerable when compared to the Leydig cells.[27],[28],[29],[30] The germinal cell division is extremely high through increased meiotic and mitotic activity, thus allowing for increased sensitivity to Cytotoxic agents [Table 1].[23],[24],[31] Sexual maturation of the testis also influences the degree of gonadal damage experienced when exposed to cytotoxic drugs, the prepuberal testis being less susceptible than post pubertal testis [Table 1].[31]
| Strategies for Fertility Preservation in Males | | |
Lack of time in case of cancer patients and lack of care provider knowledge on infertility risk have been identified as the main barriers for fertility preservation in patient care.[23],[32] Enhanced communication between oncologist and reproductive specialists leads to increased patient referrals and acceptance rates.[23],[33]
Semen banking is a choice for male cancer patients capable of producing a semen sample before commencing cancer treatment. Semen banking should be done before chemo/radiotherapy is initiated. When young males are unable to ejaculate, electroejaculation or epididymal or testicular sperm extraction may be done.[34] The frozen semen sample can be utilized for either artificial insemination or intracytoplasmic sperm injection with varied pregnancy rates. Semen sample can be stored indefinitely in liquid nitrogen.[33] Patients can opt to come back after cancer remission to continue journey to parenthood.[35]
| Fertility Preservation in Prepubertal Males | | |
In prepubertal males, dialogue with patient and parents is shown to be critical for informed decision-making. Parents and patients must be informed about the experimental nature of fertility preservation in prepubertal boys.[36] The possible further use of frozen testicular tissue remaining a research activity should be discussed. In peripubertal boys, it is possible to freeze spermatozoa after sperm collection by masturbation or testicular sperm extraction. Testicular sperm extraction can also be combined with testicular tissue freezing in order to store SSCs if no sperm is retrieved during the surgery.[36],[37],[38]
In prepubertal boys who do not produce spermatozoa, testicular tissue freezing with the objective of preserving SSCs can be performed. Testicular tissue biopsy is preferably unilateral and is done according to local surgical procedures.[36],[37],[39] Cryopreservation of testicular tissue provides opportunity to pursue either cell or tissue-based therapies in future.[6],[36]
At present, no standardized protocol has been established for human testicular tissue freezing in terms of optimal cryopreservation techniques or fertility restoration procedures to be able to generate spermatozoa. However, the most commonly used freezing protocol is controlled slow freezing with seeding.[36],[40],[41]
Transplantation method has been adapted for human testis, and the efficiency and safety of the technique are being evaluated in mouse and primate models.[36],[42] Data have been collected from 24 coordinating centers worldwide which are actively offering testicular tissue cryopreservation to safeguard the future fertility of boys.[36] There has been a 4-fold increase in the number of patients stored testicular tissue since 2012. More than 1033 young patients between 3 months and 18 years have already undergone testicular tissue retrieval and storage for fertility preservation.[36] Approaches which are under extensive research include in vitro culture or autologous transplant of testicular tissue or cells.
| Gunasheela Surgical and Maternity Hospital Experience in Fertility Preservation Services in Males | | |
At Gunasheela Surgical and Maternity Hospital, 461 male patients diagnosed with cancer (15–45 years) opted for sperm banking services before starting their cancer treatment between 2008 and 2020. Semen specimen was collected by masturbation after being recommended to maintain 2–3 days of abstinence. Before these samples could be frozen, these samples were subjected to semen analysis, where key semen parameters were analyzed. These data were tabulated with their corresponding cancer types. Sperm concentration was seen to be lower in testicular cancer compared to hematological cancers (Hodgkin's disease, non-Hodgkin's disease, leukemia, and lymphoma) and other cancers (head-and-neck cancer, bone and soft-tissue cancer, neurological cancer, gastrointestinal cancer, lung cancer, thyroid cancer, and penile cancer). Testicular cancer patients also presented with the largest semen disorder diagnosis (asthenozoospermia, oligoasthenozoospermia, oligozoospermia, and azoospermia) compared to two other groups. Males with testicular cancer are shown to have a lower semen quality between cancer groups and compared to WHO criteria, increasing their likelihood of them being infertile.
| American Society of Clinical Oncology Recommendation in Males (2018) | | |
- Health-care providers caring for adult and pediatric patients with cancer should address the possibility of infertility as early as possible before treatment starts[6]
- Health-care providers should refer patients who express an interest in fertility preservation to reproductive specialists
- Sperm cryopreservation: Sperm cryopreservation is effective, and health-care providers should discuss sperm banking with postpubertal males receiving cancer treatment
- Hormonal gonadoprotection: Hormonal therapy in men is not successful in preserving fertility. It is not recommended
- Other methods to preserve male fertility, such as testicular tissue cryopreservation and reimplantation or grafting of human testicular tissue, should be performed only as part of clinical trials or approved experimental protocols
- Postchemotherapy: Men should be advised of a potentially higher risk of genetic damage in sperm collected after initiation of therapy.
| Ethical and Moral Constrains in Oncofertility Care | | |
Gamete storage for extended periods generates ethical and moral questions that need attention, before a patient opts for a fertility preservation service. Clinical staff should offer discussions to patients which includes uncertainties regarding experimental strategies and the future use of the germs cells in the face of the possibility of the death of their biological owner.[43]
Although cryopreserved sperm can remain viable for many years, experience with these techniques is too recent to ensure its security and its routine use.[16] Questions such as:
- How long will cryopreserved sperm stay viable?
- Will the freezing and thawing process affect the quality and function of the sperm?
- What is the safety profile of the embryos created using the sperm that were frozen for prolonged period of time?
These questions can be only answered with time and experience in this field.
| Conclusion | | |
Any malignancy per say will compromise semen quality in males causing infertility or subfertility. This review addresses the gondotoxic nature of cancer therapy and the currently available options of fertility preservation in males such as semen and testicular tissue cryopreservation.
Techniques such as testicular tissue cryopreservation or freezing SSCs in prepubertal males are still experimental. The current American Society of Clinical Oncology guidelines recommend semen should be frozen in young males affected by cancer. There are ethical issues which will have to be discussed with patients on an individualized base.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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