{"paper_id":"71915f68-0bdf-4e1b-8a34-2288c5f4effb","body_text":"Chemotherapy is a potent and systemic treatment used to target rapidly dividing\ncancer cells, but it can inadvertently affect healthy cells in the body, such as\ncells in the reproductive system ( Mustapha\n et al. , 2021 ). Both men and women have reproductive\ncells that are sensitive to chemotherapy, and the damage caused by these drugs can\nlead to temporary or permanent infertility. This unintended consequence is due to\nchemotherapy’s mechanism of action, which targets not just cancer cells but any\nother cells, including those responsible for oocyte and sperm production ( Papathanasiou  et al. , 2024 ).\nThe risk of infertility depends on several factors, including the specific drugs\nused, the dosage, the patient’s age, and their pre-existing fertility health ( Papathanasiou  et al. ,\n2024 ).\nIn women, chemotherapy primarily affects the ovaries, which contain a finite number\nof oocytes from birth ( Papathanasiou  et\nal. , 2024 ). These oocytes do not regenerate, so any damage\nto them is permanent. Chemotherapy drugs, particularly alkylating agents such as\ncyclophosphamide, can cause significant ovarian toxicity by damaging the DNA in\noocytes or triggering cell death ( Markowska\n et al. , 2024 ). As a result, chemotherapy can reduce\nthe ovarian reserve, leading to diminished fertility or even premature ovarian\nfailure (POF), which is an early onset of menopause ( Horan, 2022 ). Women undergoing chemotherapy may experience temporary\namenorrhea, but in some cases, this can become permanent. The extent of damage is\noften age-dependent; younger women tend to have a better chance of recovering\nfertility after treatment, whereas older women, who have fewer oocytes, are at a\ngreater risk of permanent infertility ( Horan,\n2022 ;  Sabetian  et al. ,\n2022a ).\nIn men, chemotherapy can severely impact spermatogenesis, the process of sperm\nproduction in the testes ( Delessard  et\nal. , 2020 ;  Yaghutian Nezhad\n et al. , 2021 ). Spermatogonia are rapidly dividing\nand thus vulnerable to chemotherapy’s effects. Chemotherapy can reduce or disrupt\nsperm production, leading to conditions like oligospermia or azoospermia ( Javed, 2020 ). Depending on the type of drug and\ndosage, this infertility may be temporary. Even if sperm production resumes,\nchemotherapy can cause genetic damage to the DNA within sperm, which raises concerns\nabout the health of future offspring ( Meistrich,\n2020 ). As with women, the age of the patient plays a significant role;\nyounger men are more likely to recover sperm production after treatment, while older\nmen may face a higher risk of irreversible infertility ( Jensen  et al. , 2022 ).\nThe type of chemotherapy drug used plays a significant role in determining fertility\noutcomes. Alkylating agents, such as cyclophosphamide and busulfan, are particularly\ndamaging to reproductive cells ( Bhardwaj  et\nal. , 2023 ;  Bahmyari\n et al. , 2024 ). Platinum-based drugs, like cisplatin,\nare also highly gonadotoxic and can cause severe ovarian or testicular damage ( Tian En  et al. , 2020 ). Other\nchemotherapy drugs, such as taxanes and anthracyclines, pose a moderate risk to\nfertility but may still cause significant reproductive harm, especially when used in\nhigh doses or combined with other treatments ( Poorvu  et al. , 2019 ). The total dose and length of\nchemotherapy also influence the likelihood of infertility, with higher doses and\nlonger treatments posing a greater risk ( Hales\n et al. , 2005 ;  Markowska  et al. , 2024 ).\nUltimately, the effects of chemotherapy on fertility can vary greatly depending on\nindividual circumstances. Age, the type of cancer, the specific chemotherapy drugs,\nand the patient’s overall reproductive health all play a role in determining whether\nfertility will be affected temporarily or permanently ( Li  et al. , 2024 ). While chemotherapy is a\ncrucial tool in the fight against cancer, its potential to cause infertility can\nhave profound psychological and emotional impacts on patients, especially those of\nreproductive age ( Goldman  et al. ,\n2015 ). Therefore, patients need to discuss their fertility concerns with\ntheir healthcare providers before beginning treatment to explore possible\npreservation options.\nTable 1  provides a comprehensive snapshot of\nthe fertility effects associated with twelve widely used chemotherapy\ndrugs-Cyclophosphamide, Doxorubicin, Paclitaxel, Cisplatin, Methotrexate,\nFluorouracil (5-FU), Vincristine, Etoposide, Bortezomib, Carboplatin, Ifosfamide,\nBleomycin, and Gemcitabine-alongside Bumetanide, a non-chemotherapy diuretic, as of\nFebruary 27, 2025. The data reveals a spectrum of reproductive impacts, ranging from\nsevere, often permanent infertility risks posed by alkylating agents like\nCyclophosphamide and Ifosfamide, to milder, potentially reversible effects from\ndrugs like Gemcitabine and Bleomycin. Platinum-based agents such as Cisplatin and\nCarboplatin show significant but varying degrees of gonadotoxicity, while targeted\ntherapies like Bortezomib and less toxic agents like Vincristine and Fluorouracil\ndemonstrate minimal direct impact on fertility ( Abdel-Latif  et al. , 2022 ; American Cancer Society and\nAmerican Society of Clinical Oncology (ASCO),  2025 ). Bumetanide stands apart with no evidence of fertility effects,\nunderscoring its distinct role outside oncology ( NHS - National Health Service, 2022 ). High-risk drugs necessitate\nproactive fertility preservation strategies, such as oocyte or sperm banking,\nparticularly for younger patients, while those with milder profiles may allow for\nnatural recovery post-treatment ( Li  et\nal. , 2024 ). However, gaps in research-especially for newer\nagents like Bortezomib and less-studied drugs like Gemcitabine-suggest a need for\nfurther investigation to fully elucidate their long-term effects, particularly in\nwomen. This table serves as a valuable resource for clinicians and patients\nnavigating treatment decisions, emphasizing the importance of individualized\ncounseling to balance cancer management with reproductive goals.\nEffects of chemotherapy drugs and bumetanide on fertility: a comprehensive\noverview of commonly used agents and their reproductive impacts.\nRecent updates in clinical practice guidelines from the American Society of Clinical\nOncology underscore the importance of discussing and offering fertility preservation\noptions to all patients of reproductive age at the time of cancer diagnosis ( Su  et al. , 2025 ). All\nguidelines endorse established methods such as embryo, oocyte, and ovarian tissue\ncryopreservation, as well as ovarian transposition ( ESHRE Guideline Group on Female Fertility Preservation  et al. ,\n2020 ;  Kieu  et al. ,\n2022 ). For females, options include embryo cryopreservation, oocyte\nfreezing, and ovarian tissue freezing. Hormonal suppression and ovarian shielding\nduring radiation may also help reduce damage. However, these methods often require\ntime-sensitive procedures, which can be challenging when urgent cancer treatment is\nneeded. For males, sperm banking is the most common and effective method, while\ntesticular sperm extraction or testicular tissue freezing may be options for those\nunable to produce a sample ( Ní\nDhonnabháin  et al. , 2022 ;  Pathak  et al. , 2023 ;  Katzir  et al. , 2024 ). The Cancer Council\nAustralia emphasizes the importance of early discussions between patients and\nhealthcare providers to explore fertility preservation before treatment begins. A\nmultidisciplinary approach involving oncologists, fertility specialists, and\ncounselors ensures patients receive comprehensive care, including psychological and\nfinancial support ( Kieu  et al. ,\n2022 ).\nThis review integrates such up-to-date guideline recommendations and pooled clinical\nevidence to provide a robust framework for assessing fertility risks and\npreservation strategies in men and women undergoing gonadotoxic treatments. Also\nincludes preclinical research using animal models to provide a comprehensive\nunderstanding of chemotherapy-induced gonadotoxicity and strategies for fertility\npreservation.\nWe searched PubMed, Scopus, Web of Science, and Embase using keywords such as\n‘chemotherapy AND fertility preservation,’ ‘gonadotoxicity,’ ‘premature ovarian\nfailure,’ and ‘oocyte cryopreservation.’ The search covered publications from\nJanuary 2015 to June 2025. Only English-language articles were included.\n\nFemale fertility is intricately tied to the health and number of ovarian follicles\ncontaining immature oocytes ( Telfer  et\nal. , 2023 ). From birth, a woman has a fixed number of\noocytes that are gradually lost throughout her life, with no possibility of\nregeneration ( Moghadam  et al. ,\n2022 ). These oocytes are highly sensitive to environmental factors,\nincluding chemotherapy, which can cause both temporary and permanent damage ( Sonigo  et al. , 2019 ).\nChemotherapy targets rapidly dividing cells, a hallmark of cancer, but this also\nmakes healthy reproductive cells vulnerable to damage ( Alimbetov  et al. , 2018 ). The extent of\nchemotherapy’s impact on fertility depends on the individual’s ovarian reserve\nbefore treatment ( Blumenfeld, 2012 ).\nThroughout a woman’s reproductive life, a small percentage of follicles are\nselected to mature and eventually release oocytes in a process known as\novulation ( Johnson, 2015 ). However, most\nfollicles never reach maturity and undergo a natural process called atresia,\nwhere they degrade and are reabsorbed by the body ( Corriero  et al. , 2021 ). This gradual\ndepletion of follicles is a normal part of the aging process, but when\naccelerated by external factors such as chemotherapy, it can significantly\nimpair fertility ( Yan  et al. ,\n2022 ). Each ovarian follicle contains an oocyte surrounded by support\ncells that help regulate its development and maturation ( Clarke, 2018 ). The health of these oocytes is critical for\nreproductive success, and damage to them can lead to infertility or diminished\nfertility. Chemotherapy, particularly certain classes of drugs, can interfere\nwith this process by damaging the DNA within oocytes or inducing apoptosis,\nreducing viable oocytes over time ( Winship\n et al. , 2018 ).\nChemotherapy drugs exert their effects by interfering with cell division and\ninducing DNA damage ( Sun  et\nal. , 2021 ). While this is crucial for killing cancer\ncells, it also impacts other rapidly dividing cells, including those in the\novaries. Among the most harmful chemotherapy agents for fertility are alkylating\nagents, which include drugs like cyclophosphamide, ifosfamide, and busulfan\n( Kapoor  et al. ,\n2025 ). These drugs work by directly binding to the DNA in cells, creating\ncross-links and breaking DNA strands, which prevents cells from dividing and\nultimately leads to cell death ( Bergamo\n et al. , 2018 ). In ovarian follicles, this can\ndestroy oocytes, causing a significant reduction in the ovarian reserve ( Monniaux, 2018 ). The ovaries are\nparticularly susceptible to chemotherapy-induced gonadotoxicity because they\ncontain cells that are in various stages of division and development. Preantral\nand antral follicles, which are the follicles closest to releasing mature\noocytes, are especially vulnerable to damage ( Das  et al. , 2023 ). These follicles require a\nprecise hormonal environment and intact DNA to complete the maturation process,\nand chemotherapy can disrupt both, either by directly damaging the oocyte’s DNA\nor by impairing the support cells and hormone production needed for development\n( Winship  et al. ,\n2018 ). One major risk posed by toxic elements is oxidative stress,\nwhich also occurs when chemotherapy drugs generate free radicals that can damage\ncellular structures, including DNA, proteins, and lipids ( Cauli, 2021 ;  Talaie\n et al. , 2025 ). Environmental factors such as air\npollution, UV radiation, and chemical toxins induce oxidative stress by\ngenerating excess reactive oxygen species, which overwhelm antioxidant defenses\nand damage cellular components like lipids, proteins, and DNA ( Alaee, 2018 ;  Banagar  et al. , 2018 ;  Alaee  et al. , 2024a ;  Khodabandeh  et al. , 2025 ). Antioxidants\nneutralize reactive oxygen species (ROS) and protect cells from oxidative damage\nby donating electrons, scavenging free radicals, and enhancing endogenous\ndefense systems ( Patil  et al. ,\n2015 ;  Flora  et al. ,\n2021 ;  Neisy  et al. ,\n2025 ;  Zahedi  et\nal. , 2025 ).\nOocytes, being long-lived cells, are particularly prone to accumulating damage\nfrom oxidative stress. This can lead to DNA mutations or other types of\nmolecular damage that not only reduce the chances of successful fertilization\nbut may also raise concerns about the quality and health of any offspring ( Musson  et al. , 2022 ).\nThe most serious consequence of chemotherapy on female fertility is the potential\nfor premature ovarian failure (POF), also known as primary ovarian insufficiency\n(POI) ( Hao  et al. ,\n2019 ). POF occurs when the ovaries stop functioning properly before the\nage of 40, leading to early menopause and a loss of fertility. The onset of POF\nis marked by the cessation of menstruation (amenorrhea), low levels of estrogen,\nand high levels of follicle-stimulating hormone (FSH), which indicate that the\novaries are no longer producing oocytes. POF can be a direct result of extensive\ndamage to the ovarian reserve caused by chemotherapy. Since women are born with\na limited number of oocytes, once these are depleted, the ovaries cannot\nregenerate them ( Monniaux, 2018 ). The\nrisk of POF is particularly high in women who receive high doses of alkylating\nagents or undergo prolonged chemotherapy regimens ( Cui  et al. , 2018 ). Women who experience\nPOF may have no remaining viable oocytes, making natural conception impossible\nand requiring alternative methods like donor oocytes or adoption to achieve\nparenthood.\nIn cases where chemotherapy does not result in complete ovarian failure, it can\nstill lead to diminished ovarian reserve (DOR) ( Spears  et al. , 2019 ). This condition is\ncharacterized by a reduction in the number of viable oocytes, which can make\nconception more difficult and reduce the chances of successful in vitro\nfertilization if fertility treatment is pursued ( Parsanezhad  et al. , 2017 ;  Al Abdali & Gowri, 2021 ;  Ashourzadeh  et al. , 2024 ).\nWomen with DOR often face shorter reproductive windows and may experience\nchallenges with oocyte quality, which further complicates efforts to conceive\n( Swan & Colino, 2022 ).\nIn addition to directly damaging oocytes, chemotherapy can disrupt the hormonal\nenvironment required for normal ovarian function ( Xiong  et al. , 2021 ). Ovarian follicles\nrely on the balanced production of several key hormones, including FSH and\nluteinizing hormone (LH), which stimulate the growth and maturation of oocytes\n( Salih & Jaafar, 2013 ;  Ma  et al. , 2023 ).\nChemotherapy can interfere with the hypothalamic-pituitary-ovarian axis,\ndisrupting the normal feedback loops that regulate these hormones ( Markowska  et al. , 2024 ).\nThis disruption can lead to irregular menstrual cycles, anovulation, and\nultimately, infertility ( Song & Li,\n2021 ). Hormonal imbalances can also contribute to temporary\namenorrhea, folliculogenesis arrest, and disruption of oocyte maturation ( Alaee  et al. , 2024b ;  Singh  et al. , 2024 ). In\nsome women, chemotherapy-induced hormonal disruptions may persist, reducing\ntheir chances of conceiving naturally even if menstruation resumes ( Markowska  et al. ,\n2024 ).\nSeveral factors determine whether chemotherapy will cause temporary or permanent\ninfertility. One of the most significant factors is the age of the patient at\nthe time of treatment ( Blumenfeld, 2002 ).\nYounger women generally have a larger ovarian reserve, which offers some\nprotection against complete ovarian failure ( Richardson  et al. , 2014 ). They are more likely to\nrecover ovarian function after chemotherapy, though this is not guaranteed.\nOlder women, particularly those approaching menopause, have fewer remaining\noocytes, making them more vulnerable to permanent infertility ( Qiao  et al. , 2014 ). The\nrisk of long-term fertility issues increases significantly for women over 35 who\nundergo chemotherapy ( Blumenfeld, 2012 ).\nThe type of chemotherapy drug used is another critical factor. Alkylating agents\nare among the most gonadotoxic, causing the greatest damage to the ovaries\n( Bhardwaj  et al. ,\n2023 ). Other chemotherapy drugs, such as platinum-based compounds\n(e.g., cisplatin) and taxanes (e.g., paclitaxel), also pose a risk but may cause\nless severe damage depending on the dosage and duration of treatment ( Rottenberg  et al. , 2021 ).\nThe overall dosage and length of chemotherapy also influence fertility outcomes\n( van den Berg  et al. ,\n2021 ). Higher doses of chemotherapy, as well as prolonged treatment\nregimens, increase the likelihood of permanent ovarian damage ( Mauri  et al. , 2020 ).\nAdditionally, combination therapies, which involve using multiple chemotherapy\nagents, are more likely to cause irreversible harm to the ovaries.  Figure 1  shows the gonadotoxic effects of\nchemotherapy drug on female fertility.\nFigure 1 Comparative gonadotoxic effects of major chemotherapy drug classes on\nfemale fertility (data have been extracted from  Mulder  et al. \n(2021) ,  Dumenigo\n et al.  (2024) ,  Himpe  et al.  (2023) , and  Santaballa  et al. \n(2022) .\nComparative gonadotoxic effects of major chemotherapy drug classes on\nfemale fertility (data have been extracted from  Mulder  et al. \n(2021) ,  Dumenigo\n et al.  (2024) ,  Himpe  et al.  (2023) , and  Santaballa  et al. \n(2022) .\n\nChemotherapy carries significant risks for male fertility ( Di Tucci  et al. , 2022 ). The primary target of\nchemotherapy in men is the process of spermatogenesis, which occurs in the testes\nand involves sperm production from precursor germ cells ( Lopes  et al. , 2021 ). These germ cells are\namong the most rapidly dividing cells in the body, making them particularly\nsusceptible to the damaging effects of any toxicants ( Mohammadi  et al. , 2023 ). The drugs used in\nchemotherapy can lead to a reduction in sperm count, known as oligospermia, or even\na complete absence of sperm in the semen, referred to as azoospermia ( Mendes  et al. , 2022 ).\nAdditionally, some chemotherapy agents can damage the DNA within sperm, raising\nconcerns about fertility and the potential for genetic abnormalities in future\noffspring ( Meistrich, 2020 ).\nThe mechanism of chemotherapy affecting male fertility revolves around its impact\non the rapidly dividing germ cells responsible for sperm production ( Duffin  et al. , 2024 ).\nChemotherapy drugs, especially those classified as alkylating agents, can\ninflict substantial damage on these cells, leading to impaired spermatogenesis\n( Sriram  et al. ,\n2024 ). By disrupting the normal cell division process, these drugs\ncan interfere with the production of healthy sperm, causing various fertility\nissues. This damage is compounded by the fact that sperm production is a\ncontinuous process; therefore, any disruption can have immediate and\nlong-lasting effects on a man’s fertility. The effects may not only result in\nreduced sperm counts but may also lead to sperm with compromised motility and\nmorphology, further diminishing the chances of successful conception ( Ben-Aharon  et al. ,\n2010 ).\nThe specific chemotherapy agents used play a critical role in determining the\ndegree of fertility impairment in men ( Figure\n2 ) ( Delessard  et\nal. , 2020 ). Alkylating agents, such as cyclophosphamide and\nchlorambucil, are known for their high gonadotoxic potential ( Sriram  et al. , 2024 ).\nThese drugs can cause long-term or even permanent infertility by damaging the\ntesticular germ cells directly ( Lorenzi\n et al. , 2021 ). The likelihood of developing\ninfertility increases with the cumulative dose and duration of treatment.\nPlatinum compounds, including cisplatin, also pose a significant risk to male\nfertility ( Tian En  et al. ,\n2020 ). These drugs can harm the spermatogenic cells, leading to both\ntemporary and, in some cases, permanent infertility ( Schrader  et al. , 2001 ). Men treated with\nthese agents may experience varying degrees of fertility impairment based on\ntheir response to treatment. Other classes of chemotherapy drugs, such as\nantimetabolites and microtubule inhibitors (e.g., vinblastine and paclitaxel),\nhave a moderate risk of inducing infertility ( Markowska  et al. , 2024 ). While many men may\nexperience temporary infertility during and after treatment, some may regain\nnormal sperm production within months. However, the timeline for recovery can\nvary significantly among individuals, with some men taking years to return to\nbaseline sperm counts, if they recover at all.\nFigure 2 Comparative gonadotoxic effects of major chemotherapy drug classes on\nmale fertility (the data have been extracted from  Himpe et al., 2023 ;  Reynolds & McKenzie,\n2023 ).\nComparative gonadotoxic effects of major chemotherapy drug classes on\nmale fertility (the data have been extracted from  Himpe et al., 2023 ;  Reynolds & McKenzie,\n2023 ).\nBeyond directly impacting sperm production, chemotherapy can induce other\nreproductive issues in men ( Mendes  et\nal. , 2022 ). One notable concern is hormonal disruption,\nparticularly regarding the production of testosterone. Chemotherapy may affect\nthe hormonal signaling pathways that regulate testosterone synthesis,\npotentially impacting sexual function, libido, and overall reproductive health\n( Babaniyi  et al. ,\n2024 ). While hormonal disruptions are less common than the direct\neffects on sperm, they can still contribute to fertility challenges and affect a\nman’s quality of life. Additionally, testicular damage can occur as a result of\nchemotherapy ( Amiri  et al. ,\n2021 ). The structural integrity of the testicles is crucial for\nproper sperm production, and any damage to the testes can further impair\nfertility. The cumulative effect of chemotherapy on both sperm production and\ntesticular health underscores the importance of monitoring reproductive health\nin men undergoing cancer treatment ( McHugh\n et al. , 2024 ).\n\nThe effects of chemotherapy on male fertility can be categorized into short-term and\nlong-term outcomes ( Yumura  et al. ,\n2023 ). In the short term, many men experience a temporary reduction in\nsperm count, motility, or quality during chemotherapy ( Yumura  et al. , 2023 ). This transient\ninfertility can be distressing, especially for men who are planning to start\nfamilies. While sperm production often resumes after the completion of chemotherapy,\nthe timeline for recovery is unpredictable ( Schlegel  et al. , 2021 ). In some cases, it can take\nseveral months to years for sperm counts to return to normal levels, and not all men\nwill fully recover their fertility. In contrast, the long-term effects of\nchemotherapy may include permanent infertility, especially in men who receive high\ndoses of gonadotoxic drugs ( Duffin  et\nal. , 2024 ). Older men are particularly vulnerable; their\nreproductive function may already be declining due to age, and chemotherapy may\nexacerbate this decline, leading to an inability to produce viable sperm after\ntreatment ( Nguyen-Powanda & Robaire,\n2020 ). The risk of long-term infertility necessitates careful\nconsideration and planning for men undergoing chemotherapy who wish to preserve\ntheir reproductive options ( Di Tucci  et\nal. , 2022 ).  Table 2 \nhighlights that chemotherapy can cause temporary fertility issues, like amenorrhea\nin women and low sperm counts in men, which often improve in younger patients.\nHowever, long-term effects, such as permanent infertility from ovarian failure or\nazoospermia, are more likely with high doses of drugs like cyclophosphamide,\nespecially in older individuals. These differences emphasize the need for early\nfertility planning to address both short-term setbacks and lasting impacts.\nRisk factors for chemotherapy-induced infertility.\nTable 3  summarizes the shortand long-term\neffects of chemotherapy on male and female fertility, while  Figure 3  illustrates the underlying mechanism of\nchemotherapy-induced infertility.\nShort-term vs. long-term effects of chemotherapy on fertility.\nFigure 3 Schematic representation of folliculogenesis and spermatogenesis\ndisruption after chemotherapy.\nSchematic representation of folliculogenesis and spermatogenesis\ndisruption after chemotherapy.\n\nChemotherapy-induced infertility is influenced by several critical factors, each\nplaying a significant role in determining the extent of reproductive damage and the\nlikelihood of fertility recovery after treatment ( Bhardwaj  et al. , 2023 ). These factors include the type\nand dosage of chemotherapy drugs used, the age of the patient, and the individual’s\npre-existing fertility health. Understanding these factors is essential for\nassessing the risk of infertility and considering fertility preservation options for\ncancer patients undergoing chemotherapy.  Table\n4  illustrates that chemotherapy-induced infertility hinges on drug type,\ndosage, age, and pre-existing fertility health. Alkylating agents and platinum\ncompounds, especially at high doses, pose the greatest threat to reproductive cells\nin both women and men, often causing irreversible damage. Older patients face higher\nrisks due to naturally declining fertility, while those with prior reproductive\nissues are more vulnerable. These factors highlight the need for tailored treatment\nplans and early fertility discussions to mitigate risks and preserve future\nreproductive options.\nComparison of fertility preservation options for women and men.\nOne of the most influential factors in chemotherapy-induced fertility loss is the\ntype and dosage of the chemotherapy drugs administered ( Di Tucci  et al. , 2022 ). Different\nchemotherapy agents vary in their level of gonadotoxicity, or their ability to\ndamage reproductive cells. Alkylating agents, such as cyclophosphamide,\nifosfamide, and busulfan, are among the most harmful to both male and female\nreproductive cells ( Olowe  et\nal. , 2024 ). These drugs work by binding to and\ncross-linking DNA, which disrupts cell division and leads to cell death. In\nreproductive cells, this process can result in the destruction of oocytes in\nwomen and sperm-producing germ cells in men, often leading to irreversible\ninfertility. Cisplatin, a platinum-based compound, also poses a high risk of\nfertility loss. While it is effective in targeting cancer cells, cisplatin is\nhighly toxic to germ cells, potentially causing long-term or permanent\ninfertility, especially when administered at high doses ( Katanić Stanković  et al. , 2023 ). The\ncumulative dose of chemotherapy is a crucial factor; the higher the dose and the\nlonger the treatment duration, the greater the risk of significant reproductive\ndamage ( van den Boogaard  et\nal. , 2022 ). For some patients, even moderate doses of\ngonadotoxic drugs can lead to a reduction in ovarian reserve or sperm count,\nmaking it essential to tailor chemotherapy regimens carefully for patients\nconcerned about fertility ( Table 2 ).\nThe age of the patient is another critical determinant of fertility loss during\nchemotherapy, particularly for women ( Lee\n et al. , 2011 ). Female fertility is closely\nlinked to the size and health of the ovarian reserve, which consists of a finite\nnumber of oocytes present from birth ( Gleicher\n et al. , 2011 ). As women age, their ovarian\nreserve naturally declines, with the quantity and quality of oocytes diminishing\nover time. Older women, especially those approaching menopause, are at higher\nrisk of permanent infertility following chemotherapy, as they may have fewer\nviable oocytes remaining before treatment even begins ( Sparidaens  et al. , 2022 ). The ovaries of\nyounger women tend to be more resilient and may have a greater capacity to\nrecover after chemotherapy, although this is not guaranteed. In men, the impact\nof age on chemotherapy-induced infertility is somewhat less pronounced but still\nimportant. Older men may experience a slower or incomplete recovery of sperm\nproduction following chemotherapy due to age-related declines in reproductive\nfunction (de  Almeida  et al. ,\n2024 ). As a result, men over the age of 40 undergoing chemotherapy\nmay face a higher risk of permanent fertility loss than younger men. Both male\nand female patients should consider their age when assessing the potential\nimpact of chemotherapy on their long-term fertility.\nA patient’s pre-existing fertility health is a significant factor in determining\ntheir susceptibility to chemotherapy-induced infertility ( Mauri  et al. , 2020 ). Individuals with\nunderlying fertility issues, such as endometriosis, polycystic ovarian syndrome\n(PCOS), or low sperm count, may be more vulnerable to the damaging effects of\nchemotherapy ( Brassard  et al. ,\n2008 ;  Shiravani  et\nal. , 2024 ). For women with conditions like\nendometriosis, where the health of the ovarian reserve may already be\ncompromised, chemotherapy can further reduce the number of viable oocytes,\nincreasing the likelihood of premature ovarian failure or diminished ovarian\nreserve ( Mustapha  et al. ,\n2021 ). Similarly, men with suboptimal sperm parameters, such as low\nsperm count or poor sperm motility, may experience a more profound impact on\ntheir fertility, as chemotherapy could exacerbate these issues ( Blumenfeld, 2012 ). Patients with\ncompromised reproductive health should be particularly cautious when undergoing\nchemotherapy and may benefit from pre-treatment fertility assessments ( Di Tucci  et al. , 2022 ).\nThese evaluations can help determine baseline fertility and guide decisions\nabout fertility preservation strategies, such as sperm banking for men or\noocyte/embryo freezing for women. By understanding their unique reproductive\nrisks, patients can make informed choices about safeguarding their fertility\nbefore beginning cancer treatment. The factors influencing fertility loss during\nchemotherapy are multifaceted and include the type and dose of chemotherapy\ndrugs, the age of the patient, and their pre-existing fertility health.\nAlkylating agents and platinum compounds pose the highest risk of reproductive\ndamage, particularly at high doses ( Tian En\n et al. , 2020 ;  Sriram  et al. , 2024 ). Recognizing these factors is\nessential for assessing fertility risks and exploring preservation options to\nprotect future reproductive potential.\n\nFertility preservation strategies are available for patients who wish to have\nbiological children after chemotherapy.\nFor patients undergoing chemotherapy who are concerned about their future\nreproductive potential, there are several medical interventions available to help\npreserve fertility. These options vary depending on the patient’s sex, age, and\nspecific circumstances, such as whether they are preor post-pubertal. Fertility\npreservation methods are critical in helping patients retain the possibility of\nhaving biological children after cancer treatment ( Klipstein  et al. , 2020 ).  Table 4  shows that fertility preservation options vary widely\nfor women and men facing chemotherapy. These options highlight the importance of\npersonalized planning to protect reproductive potential before cancer treatment\nbegins.\nFortunately, several fertility preservation strategies are available for women\nundergoing chemotherapy ( Razeti  et\nal. , 2023 ). The effectiveness and suitability of each\ndepend on factors like age, ovarian reserve, and the type of chemotherapy being\nadministered. Oocyte cryopreservation is one of the most common methods ( Cho  et al. , 2020 ). This\ninvolves stimulating the ovaries with hormones to produce multiple oocytes,\nwhich are then retrieved and frozen for future use. This technique allows women\nto preserve their oocytes before undergoing chemotherapy, providing an\nopportunity to conceive through IVF later (11). Another option is embryo\nfreezing, which is similar to oocyte freezing but involves fertilizing the\nretrieved oocytes with sperm to create embryos before freezing them ( Cho  et al. , 2020 ). This\napproach is typically chosen by women who have a partner or wish to use donor\nsperm. Ovarian tissue cryopreservation is an emerging experimental technique\nwhere ovarian tissue is removed, frozen, and reimplanted after treatment to\nrestore ovarian function ( Eijkenboom  et\nal. , 2022 ). This method is particularly useful for\nprepubescent girls who cannot undergo oocyte retrieval but still wish to\npreserve fertility. A significant concern with ovarian tissue transplantation is\nthe potential reintroduction of malignant cells. To mitigate this risk,\nalternative approaches have been developed. Following ovarian tissue\ncryopreservation, follicles can be isolated and cultured in vitro, enabling\ntheir maturation without the need for tissue retransplantation. This technique\neliminates the risk of cancer cell transfer while preserving fertility potential\n( Telfer  et al. ,\n2023 ). In vitro maturation of oocytes from unstimulated or minimally\nstimulated ovaries offers another promising approach, particularly for patients\nwho cannot undergo conventional ovarian stimulation.\nNew frontier approaches, including artificial ovary constructs using\nbiomaterials, 3D scaffolds, and ovary-on-a-chip systems, are being explored to\nrestore ovarian function and growth of follicles ex vivo ( Dadashzadeh  et al. , 2021 ).\nTissue engineering strategies using decellularized ovarian scaffolds are being\ndeveloped to create a supportive microenvironment for follicular development\nwhile eliminating cancer cells ( Alaee  et\nal. , 2021 ; 2024b). These acellular matrices, when\nrepopulated with patient-derived follicles or ovarian cells, may restore\nendocrine function and fertility without the risk of cancer recurrence ( Dadashzadeh  et al. , 2021 ).\nOther scaffold-based approaches incorporating biomaterials like alginate or\nfibrin aim to mimic the ovarian extracellular matrix to support follicle\nsurvival and growth ( Dadashzadeh  et\nal. , 2021 ). These emerging technologies represent\nimportant alternatives to traditional transplantation of cryopreserved ovarian\ntissue, particularly for patients with blood-borne malignancies where the risk\nof malignant cell transfer remains a significant concern ( Kuchakzadeh  et al. , 2024 ).\nFor some women, the use of GnRH agonists (gonadotropin-releasing hormone\nagonists) during chemotherapy may help protect the ovaries by temporarily\nsuppressing ovarian function ( Lee & Choi,\n2021 ). By shutting down the ovaries and reducing hormonal\nstimulation, GnRH agonists aim to shield oocytes from chemotherapy’s damaging\neffects. However, the effectiveness of this approach is still under\ninvestigation and may not provide complete protection against fertility loss\n( Lee & Choi, 2021 ).\nMen undergoing chemotherapy also have a range of fertility preservation options,\nwith sperm banking being the most common and well-established technique ( Jensen  et al. , 2022 ).\nThe most common fertility preservation method for men is sperm banking, which\ninvolves collecting and freezing sperm samples before starting chemotherapy\n( Liu  et al. , 2021 ).\nThe sperm can be stored for extended periods and used later in assisted\nreproductive technologies, such as in vitro fertilization or intracytoplasmic\nsperm injection ( Moungala, 2023 ). Sperm\ncryopreservation is a straightforward and effective option for men, with success\nrates for conception remaining high even after long-term storage ( Akbarzadeh-Jahromi  et al. ,\n2022 ;  Moungala, 2022 ). For\nmen who can produce sperm, this method is highly recommended before undergoing\nchemotherapy, as sperm production may be impaired or lost permanently after\ntreatment ( Sharma & Sharma,\n2020 ).\nFor prepubescent boys who have not yet begun producing sperm, traditional sperm\nbanking is not an option. In such cases, an experimental technique known as\ntesticular tissue freezing may be considered ( Saulnier  et al. , 2021 ). This procedure involves\nsurgically removing a small portion of testicular tissue that contains sperm\nprecursor cells, which are immature cells that have the potential to develop\ninto mature sperm eventually ( Mitchell &\nIves, 2024 ). The tissue is then frozen and stored for future use,\nwith the hope that advances in reproductive technology will allow these\nprecursor cells to be used to restore fertility or generate viable sperm in the\nfuture. While this method is still in the experimental stages, it offers hope\nfor young boys who would otherwise face a high risk of infertility due to cancer\ntreatment ( Mitchell & Ives,\n2024 ).\nSuccessful testicular tissue reconstruction for the reintroduction of\ncryopreserved spermatogonial stem cells is a critical step towards restoring\nfertility ( Forouzandegan  et\nal. , 2025 ). This process typically involves the enzymatic\ndigestion of a sterile testicular cell suspension, which is then co-cultured\nwith supportive somatic cells and often integrated into a three-dimensional\nbiomaterial scaffold, such as decellularized testis, agarose, or Matrigel, to\nreform a tissue-like structure ( Del Vento\n et al. , 2018 ). Following in vitro culture to\nallow for cell aggregation and reorganization, this reconstructed tissue is\nsubsequently grafted, often subcutaneously or under the tunica albuginea, into\nan immunodeficient mouse host ( Del Vento\n et al. , 2018 ). This in vivo environment provides\nthe necessary physiological signals and vascularization to support the survival,\nengraftment, and crucially, the initiation of spermatogenesis from the\ntransplanted spermatogonial stem cells, thereby validating the functional\npotential of the reconstructed testicular niche ( Izadi  et al. , 2025 ).\nImproving the success of fertility preservation via sperm and oocyte\ncryopreservation requires a multi-pronged approach that addresses both\nlogistical and biological challenges. A primary strategy is the urgent timeline\noptimization between diagnosis and the start of therapy to harvest gametes at\nthe highest possible quality ( Ozimic  et\nal. , 2023 ). For post-pubertal males, this means multiple\nsperm collections if time permits, while for females, random-start ovarian\nstimulation protocols have revolutionized the process by allowing immediate\ninitiation of cycle synchronization, shaving weeks off the timeline ( Walker  et al. , 2022 ).\nBiologically, the administration of antioxidants is a key intervention to\ncounteract the oxidative stress induced by both the disease state and cancer\ntreatments themselves. Supplementation with compounds like Coenzyme Q10,\nMelatonin, and Vitamin E can help protect mitochondrial function in oocytes and\nreduce DNA fragmentation in sperm, thereby improving post-thaw survival and\ndevelopmental competence ( Karimfar  et\nal. , 2015 ;  Cao\n et al. , 2022 ;  Zhang  et al. , 2024 ).\n\nAfter chemotherapy, patients who wish to conceive may undergo fertility assessments\nto determine whether natural conception is possible. In cases where infertility is\ndiagnosed, assisted reproductive technologies such as in vitro fertilization, sperm\nretrieval, or donor oocytes/sperm may be explored.\n\nInfertility resulting from chemotherapy can have profound psychological and emotional\nconsequences, particularly for young cancer survivors who have aspirations for\nfuture parenthood ( Banser, 2022 ). Getting a\ncancer diagnosis can make people scared and unsure. Finding out they might not be\nable to have kids can make them feel even more sad, lost, and hopeless. Many people\nfeel angry, sad, or worried when they realize they might not be able to have kids.\nFor young people who beat cancer, not being able to have kids can affect more than\njust their feelings-it can also change things with their partner, family, and\nfriends. The stress of trying to have a baby, along with the tough physical and\nemotional effects of cancer treatment, can put pressure on close relationships.\nPartners might not get the emotional side of not having kids, which can leave the\nperson feeling alone. Doctors and nurses are really important in helping with these\nemotional struggles. They need to talk to patients about ways to save fertility and\nthe chance of not having kids before starting chemo. These talks can help patients\nmake smart choices about having kids later. Also, giving patients counseling or\nsupport groups can help them deal with their sadness and worries. Support groups can\nbe particularly beneficial as they create a safe space for individuals to share\ntheir experiences and feelings with others who are facing similar challenges. These\nconnections can help combat feelings of isolation and foster a sense of community.\nMental health professionals trained in reproductive health can also offer\ntherapeutic interventions tailored to the unique experiences of cancer survivors,\nhelping them process their emotions and navigate the complexities of infertility\n( Banser, 2022 ;  Dong  et al. , 2023 ;  Ensafdaran  et al. , 2024 ). Overall, recognizing\nthe psychological and emotional impact of infertility is vital in providing\ncomprehensive care to cancer survivors. By addressing these issues, healthcare\nproviders can help individuals regain a sense of control and hope for the future,\nwhether that involves exploring alternative paths to parenthood or finding peace\nwith their situation.\nLow-income patients, rural residents, and those without health insurance often face\nsignificant barriers to timely fertility preservation, including high out-of-pocket\ncosts, lack of nearby specialized clinics, and the need to travel long distances to\naccess reproductive services ( Peipert  et\nal. , 2023 ). Studies from multiple countries have reported\nthat patients from socioeconomically disadvantaged backgrounds are less likely to be\nreferred to fertility specialists compared with those from higher-income groups\n( Flanagan  et al. , 2022 ).\nGeographic disparities also play a major role, as rural or remote communities may\nhave limited or no knowledge and access to reproductive endocrinologists or\ncryopreservation facilities, leading to delayed or missed opportunities for\nfertility preservation before cancer treatment ( Letourneau  et al. , 2012 ;  Alaee  et al. , 2019 ). In addition, cultural\nnorms, language differences, and lack of awareness among patients and healthcare\nproviders can further reduce the likelihood of timely referral and intervention\n( Letourneau  et al. ,\n2012 ). Variations in national health policies and insurance coverage add\nanother layer of inequality, with some healthcare systems fully covering fertility\npreservation costs, while others provide no reimbursement, making such ( Gadson  et al. , 2024 ).\n\nThe advent of nanoparticle-based cancer therapies represents a monumental leap\nforward in oncology, offering the potential for highly targeted drug delivery that\nmaximizes tumor destruction while minimizing the systemic side effects that have\nlong plagued conventional treatments like chemotherapy and radiation ( Abbasi, 2017 ;  Taghipour  et al. , 2017 ). By engineering these\nmicroscopic carriers to seek out and penetrate cancerous cells specifically,\nphysicians can administer powerful cytotoxic agents with unprecedented precision\n( Abdollahii  et al. ,\n2020 ). This targeted approach spares much of the body’s healthy tissues from\nexposure, thereby reducing the severity of common side effects such as nausea, nerve\ndamage, and extreme fatigue ( Andone  et\nal. , 2023 ). The promise of nanoparticles lies in their\nability to make cancer treatment more effective and more tolerable, potentially\nturning certain cancers into manageable chronic conditions ( Andone  et al. , 2023 ).\nHowever, this significant progress introduces a complex and serious secondary\nconcern: the potential risk of infertility ( Falchi\n et al. , 2018 ;  Ilani\n et al. , 2018 ). While nanoparticles are designed for\nspecificity, their small size and unique pharmacokinetic properties raise questions\nabout unintended biodistribution. Studies have shown that some nanoparticles,\nparticularly those with poorly optimized formulations, may impair spermatogenesis by\ncausing oxidative stress and DNA damage ( Ilani &\nAlaee, 2017 ;  Falchi  et\nal. , 2018 ). Nanoparticles can cross biological barriers,\nsuch as the blood-testis barrier, and accumulate in reproductive tissues, which can\nbe harmful. Studies have shown that some nanoparticles, particularly those with\npoorly optimized formulations, may impair spermatogenesis by causing oxidative\nstress and DNA damage ( Falchi  et\nal. , 2018 ). This can lead to oligospermia, azoospermia, or\nabnormal sperm morphology, ultimately reducing male fertility ( Sabetian  et al. , 2022b ). In women, the impact\nof nanoparticles on ovarian function and oocyte quality is less well understood, but\nconcerns have been raised about their potential to disrupt the ovarian environment\nor harm oocytes. While nanoparticles offer groundbreaking potential in cancer\ntreatment and even in diagnosing and treating infertility, their use must be\ncarefully optimized to avoid harming reproductive health.\nResearchers are working on refining nanoparticle formulations, incorporating\nantioxidants, vitamins, or other protective agents to reduce toxicity ( Sabetian  et al. , 2021 ).\nThis improved detection helps in the early diagnosis of both male and female\ninfertility, leading to more timely and effective treatments. In therapeutic\napplications, nanoparticles can be designed to deliver targeted drugs to tissues\n( Taghipour  et al. ,\n2017 ). For example, gold, zinc, silver, and cerium nanoparticles are under\ninvestigation for their ability to enhance sperm quality or protect oocytes from\noxidative damage during assisted reproductive technologies, but some of them have\nadverse effects ( Davis  et al. ,\n2024 ).\nConsequently, the development and deployment of these innovative treatments must be\npaired with proactive fertility preservation strategies. For patients of\nreproductive age, this means oncologists must integrate discussions about\ninfertility risks into the informed consent process before starting treatment. The\nscientific community is also obligated to conduct rigorous long-term toxicology\nstudies focused specifically on the gonadal impact of various nanoparticle\nformulations. Ultimately, the goal is to harness the life-saving power of\nnanotechnology without sacrificing the possibility of future life, ensuring that\nbeating cancer does not come at the cost of a patient’s ability to build a\nfamily.\n\nChemotherapy is a vital tool in combating cancer, yet its impact on fertility\nrepresents a significant challenge for patients of reproductive age. This review\nhighlights how chemotherapy, particularly through alkylating agent compounds,\ndisrupts ovarian function and spermatogenesis, often leading to diminished fertility\nor permanent infertility. The risk is modulated by factors such as drug type,\ndosage, patient age, and baseline fertility, with younger patients showing greater\npotential for recovery. Advances in fertility preservation, including oocyte,\nembryo, and sperm cryopreservation, alongside experimental techniques like ovarian\nand testicular tissue freezing, provide viable options for safeguarding reproductive\npotential. However, the emotional toll of infertility underscores the importance of\npre-treatment counseling and psychological support. Ultimately, a multidisciplinary\napproach-integrating oncology, reproductive medicine, and mental health support-is\nessential to address the complex interplay between cancer treatment and fertility,\nempowering patients to make informed decisions about their reproductive futures.","source_license":"CC-BY-4.0","license_restricted":false}