Thus, clinicians should be able to counsel patients with accurate, up-to-date evidence about this critical issue. Several recent reviews of fertility preservation strategies have been published 4—7 and guidelines crafted 8— However, to our knowledge, there is no recent evaluation regarding the risk of infertility associated with specific diseases and therapies among different age groups.
This review synthesizes the literature and summarizes the current best estimates of fertility risk from modern day cancer treatment for children and adults to enable clinicians to counsel patients with the most up-to-date understanding of their risks and the potential indication for fertility preservation. We performed a review of published articles describing the risks of cancer treatments to female and male fertility using the PubMed database.
Search terms included, but were not limited to, names of malignancies eg, breast cancer, leukemia , cancer therapies eg, chemotherapies, hormone therapies, biologics, and radiation techniques , and outcomes eg, pregnancies, birth, fertility, infertility, amenorrhea, azoospermia. We included only peer-reviewed articles written in English.
No date cutoff was imposed. Reference lists were reviewed for additional relevant articles. All study designs were considered. Randomized trials and prospective observational studies were included preferentially over retrospective studies.
For the purposes of this review, the primary outcome of interest is fertility the ability to conceive a child , and we thus report pregnancy and live birth data whenever possible and use surrogates, such as amenorrhea, semen parameters, and laboratory markers of gonadal insufficiency, as alternatives when necessary Figure 1. Findings are broken down by sex and age group pediatric vs adult and by cancer type for ease of reference.
They are further grouped by general degree of risk high, intermediate, and low as detailed in Figures 2—4 and color-coded. Risks to female fertility associated with cancer treatments. Data from prior prospective and retrospective trials inform the risks of infertility, yet limitations exist in assessing the likelihood that an individual patient will remain fertile. Ovarian reserve varies among women and is affected by additional factors, including genetic polymorphisms associated with age of menopause 11 and others in genes encoding drug metabolism enzymes 12 , 13 may also affect risk of ovarian toxicity.
Psychosocial factors, many of which are affected by cancer diagnosis and treatment, are also important determinants of reproductive choices and may have important implications when comparing fecundity of survivors to control populations Due to ease of measurement, amenorrhea is frequently reported as a primary outcome yet is an imperfect predictor of fertility. Female survivors who have spontaneous menses, particularly if irregular, may still have decreased ovarian reserve and reproductive potential 15— Abnormalities of traditional laboratory markers such as follicle-stimulating hormone, estradiol, and inhibin-B levels are late markers of ovarian aging Anti-Mullerian hormone AMH is more strongly correlated with antral follicle count 21 and is an earlier predictor of decreased ovarian reserve AMH is evaluable in both pre- and postmenarchal females 23 and detects diminished ovarian reserve among female cancer survivors 17 , 18 , 24 , AMH may therefore be a preferred laboratory assay for establishing a pretreatment baseline, assessing ovarian reserve among survivors, and determining who might benefit from fertility preservation services The following section details data regarding fertility risks in select populations, diseases, and treatments and is presented with a summary in Figure 2.
Multiple reports from the Childhood Cancer Survivor Study CCSS , a multi-institutional long-term follow-up study that included patients and matched sibling control subjects, have demonstrated associations between chemotherapy use, as measured by summed alkylating agent dose or cyclophosphamide equivalent dose CED , and risk of clinical infertility, never achieving pregnancy, and premature menopause 27— Most studies support the impact of alkylating chemotherapy on infertility and surrogates, including acute ovarian failure AOF and premature menopause 19 , 31—33 , but not all have identified a detrimental effect 34 , The CCSS report did not identify an association between platinum agents cisplatin, carboplatin and the likelihood of pregnancy in female childhood cancer survivors However, females with germ cell tumors were not included, and whether platinum administered in this setting following unilateral oophorectomy affects future fertility remains unknown.
The CCSS represents the most robust source of data, and considering the body of literature, there is strong evidence that higher levels of exposure to alkylating chemotherapy have a greater effect on fertility and biological surrogates.
Estimated risk to male and female fertility from select pediatric chemotherapy regimens using calculated cyclophosphamide equivalent dose CED and cisplatin exposures. Patient and disease factors appear to have little impact upon subsequent fertility outcomes among children. Age at diagnosis is an important predictor of fertility-related outcomes in some adult malignancies; however, data from the CCSS showed no association between age at diagnosis and future fertility Although HL has been found to be an independent risk factor for premature menopause and is associated with diminished pretreatment ovarian reserve in adult women 29 , 37 , a large prospective cohort study of female childhood HL survivors found that rates of parenthood were comparable to the German general population through age 39 years, suggesting that the impact of HL and its treatment on fertility is not substantial until the majority of the reproductive years have passed Furthermore, regimens that include alkylating chemotherapy, which are associated with lower AMH values relative to doxorubicin, bleomycin, vinblastine, dacarbazine ABVD 25 , are being used less frequently in modern therapy, limiting the impact upon fertility.
Among adults, the most robust data regarding fertility risks are available for women with breast cancer. Thus, when considering absolute rates of TRA, the age distribution of study populations must be considered.
Cyclophosphamide, included in most adjuvant regimens, appears to be the primary driver of TRA. How much cyclophosphamide and how it is administered also appears to contribute to heterogeneity in early and late surrogates of ovarian toxicity.
Additional data inform the risks of TRA with taxanes, which are now frequently included in adjuvant regimens. Although some reports have identified taxanes as an independent risk factor 41 , 46 , most have not 42 , 43 , 45 , 51— Recognizing limitations in the literature, especially studies grouping paclitaxel and docetaxel, the available data suggest taxanes may contribute to TRA, but that the absolute effect appears to be small and the predominant predictors of amenorrhea for women receiving taxane-containing chemotherapy are age and exposure to alkylating chemotherapy.
Neither dose-dense schedule nor the addition of trastuzumab has been associated with TRA 47 , Platinum agents are increasingly being explored for triple negative breast cancer and it will be important to characterize their impact on TRA. Cisplatin, a DNA cross-linking agent, appears gonadotoxic in some settings, though published data are scarce 56 , Cisplatin was associated with reduced pregnancy rates in males, but not females, in the CCSS 30 , 57 , Given the limited data and plausible mechanism of gonadotoxicity, it is most appropriate to counsel patients that platinum agents, particularly cisplatin, may impair fertility.
Tamoxifen use following adjuvant chemotherapy is associated with a 2-fold increase in risk of TRA 40 , 41 , 47 , 60 , though no women age 40 years or younger treated with tamoxifen alone developed amenorrhea within a large prospective cohort study Tamoxifen does not appear to have permanent effects on menstrual function or fertility but is teratogenic and must be held before and during pregnancy; thus, the need to delay childbearing can pose a risk to fertility through ovarian aging.
Ovarian suppression with GnRH agonists is increasingly being incorporated into the treatment of premenopausal women with hormone-sensitive disease 62 , Although chemotherapy has often been the default approach for young women, optimization of endocrine therapy with ovarian suppression may be a more prudent approach for some with lower risk disease and a means of preserving future fertility.
In the treatment of cervical cancer, the focus for women interested in future fertility has been on prevention of anatomical changes that impair childbearing. Fertility-sparing procedures, such as vaginal or abdominal radical trachelectomy in which the cervix and upper vagina are removed, are now options for highly selected patients Whereas all women in one series required in vitro fertilization IVF after treatment, 16 of 17 patients who conceived in another series did so naturally 68 , Candidates for fertility-sparing procedures generally do not receive adjuvant radiation or chemotherapy Pregnancy data are not available for women receiving definitive concurrent chemoradiation.
A small series demonstrated the feasibility of ovarian transposition before chemoradiation, with ovarian failure experienced by 1 of 7 women age 40 years or younger and 6 of 7 women aged over 40 years Although hysterectomy with bilateral salpingo-oophorectomy represents the standard approach to localized endometrial cancer, continuous progestin therapy is a fertility-sparing option for highly selected young women with endometrial hyperplasia or stage IA endometrial adenocarcinoma Management of epithelial ovarian cancer also includes removal of critical reproductive organs.
For highly selected women, depending on extent and type of disease, fertility-sparing procedures with unilateral salpingo-oophorectomy and complete surgical staging may be performed In one study of women with unilateral stage I invasive epithelial ovarian cancer, of women Gonadal-sparing surgery is the goal of management of ovarian cyst and tumors in adolescent and young adult women.
Most ovarian tumors in girls and adolescents are benign. Malignant tumors are usually of germ cell origin. For tumor marker negative tumors, a fertility-sparing procedure can be performed. With positive tumor markers, a unilateral oophorectomy and staging procedure—in which peritoneal fluid is collected, lymph nodes and omentum are inspected, and biopsy reserved for suspicious sites—is performed to maintain fertility.
Minimizing abdominopelvic surgery prevents fertility issues due to adhesions. For women requiring further treatment, fertility preservation should be considered, given the effect of cisplatin on ovarian function remains unknown in this setting. Thyroidectomy represents the primary treatment for localized, differentiated thyroid cancer and, with thyroid hormone replacement, is not gonadotoxic.
The average age of menopause is slightly lower following I The majority of adult women diagnosed with HL are of reproductive age and, given their excellent cancer prognosis, fertility in survivorship may be particularly important A robust literature demonstrates that TRA among HL survivors is affected by age, systemic therapy, and exposure to pelvic radiation 16 , 96 , Thus, fertility preservation is usually not needed for women receiving ABVD alone.
Ongoing trials integrating targeted and immune-based therapies such as brentuximab and nivolumab into upfront HL therapy, both of which are unlikely to directly affect fertility, may further limit the need for gonadotoxic alkylating chemotherapy. Non-Hodgkin lymphoma NHL encompasses indolent and aggressive diseases addressed with a variety of treatments, including chemotherapy, targeted therapies, and immune-based therapies.
Older women are more likely to experience AOF Women treated with rituximab, an anti-CD20 monoclonal antibody, are counseled to avoid pregnancy given concerns regarding teratogenicity and immunosuppression of offspring No data are available regarding the impact of rituximab on female fertility, though the mechanism of action would not be expected to directly affect fertility.
Treatment of relapsed NHL and HL with chemotherapy or autologous hematopoietic cell transplantation HCT is clearly associated with worse reproductive outcomes due largely to greater use of alkylator chemotherapy.
The backbone treatment for acute myeloid leukemia other than acute promyelocytic leukemia remains daunorubicin, an anthracycline, and cytarabine. Fertility risks associated with anthracyclines are poorly defined because anthracyclines have usually been co-administered with alkylators for more prevalent cancers.
However, rates of amenorrhea with anthracyclines may be substantial even in the absence of alkylators Treatment of ALL often includes alkylating agents and risk presumably varies by the regimen selected. The greatest threat to fertility among women with leukemia is gonadotoxic conditioning before HCT, as exhibited by lower rates of infertility among women who receive consolidation chemotherapy The urgency to initiate induction therapy generally precludes standard fertility preservation measures for women with acute leukemia, but opportunities may exist in the first complete remission or before induction therapy for those with high-risk myelodysplasia, especially because pregnancies can be achieved after HCT with banked embryos or oocytes The risk to fertility associated with long-term imatinib, a tyrosine kinase inhibitor TKI targeting bcr-abl, for chronic myeloid leukemia is not well studied.
Offspring of women exposed to imatinib during pregnancy have demonstrated congenital abnormalities, and patients should practice reliable contraception while on TKI therapy, including imatinib or others — Despite case reports of impaired ovarian function and premature ovarian failure , it is not clear whether imatinib or other TKIs affect fertility.
Patients who discontinue are at risk for loss of response ; thus, the benefit of continuing therapy during reproductive years represents a threat to fertility and consideration can be given to alternative strategies for having future biologic children, including use of a gestational carrier.
Survivors who undergo HCT are at high risk for ovarian failure and infertility due to the treatment of their primary disease and the conditioning regimen, which generally includes gonadotoxic chemotherapy with or without radiation. However, many pregnancies have been identified following HCT, including autologous and nonmyeloablative and myeloablative allogeneic transplants for malignant and nonmalignant conditions — True risks of infertility and amenorrhea have been difficult to assess given heterogeneous patient populations and that not all survivors desire or attempt pregnancy Thus, although fertility may be severely impaired by transplant, risk varies considerably by age and conditioning regimen.
All females undergoing HCT should be assumed to be at intermediate to high risk of ovarian failure and infertility, and additional research is needed to help risk-stratify women based on patient, disease, and treatment characteristics. Radiation can diminish fertility when directed to reproductive organs or the structures that produce hormones necessary for reproduction. The exposure required to induce ovarian failure and infertility decreases with increased age, due to the normal decline in ovarian reserve and an increase in radiosensitivity of oocytes in growing follicles relative to primordial oocytes — TRA occurred in all 11 women within the Georgia Cancer Registry exposed to pelvic radiation for a variety of malignancies Pelvic radiation may also affect the uterus, leading to atrophy of the myometrium and endometrium and decreased uterine length and blood flow , The degree to which uterine effects contribute is unclear, though patients treated with pelvic radiation are known to be at substantial risk for pregnancy complications Cranial irradiation affects fertility through the development of endocrinopathies involving the hypothalamic-pituitary-gonadal axis Whether the decreased radiation doses currently used for PCI and implementation of proton radiotherapy for CNS malignancies will mitigate fertility risk remains unknown Infertility among male cancer survivors is common yet has been the subject of less research than female infertility.
Pregnancy and live birth data are sparse, and spermatogenesis parameters are frequently used as surrogates although generally felt to be more reliable than markers of ovarian reserve.
Semen analysis methodology and reference ranges for semen volume, sperm concentration, total sperm number, morphology, and motility have been standardized , Today, use of in vitro fertilization and intracytoplasmic sperm injection overcome most sperm defects and allow successful pregnancy.
Semen analysis does not assess the cellular and biochemical processes required to bind, penetrate, and fertilize the oocyte or genetic contributors to infertility ; thus, a normal semen analysis does not guarantee fertility.
Although treatment usually represents the greatest threat to fertility of male survivors, the underlying malignancy may affect semen production and quality through poorly understood mechanisms. Similarly, HL is associated with oligospermia and azoospermia before treatment — Interestingly, treatment of the underlying malignancy may yield improvements in spermatogenesis — Radiation and chemotherapy have cytotoxic effects on testicular germinal epithelium including Sertoli cells, but to a lesser extent on Leydig cells, leading to frequent impairment of spermatogenesis without hypogonadism , Lack of early recovery does not necessarily portend permanent sterility.
The next section details data regarding the risk to male infertility in select populations, diseases, and associated treatment modalities and is presented with a summary in Figure 4. Risks to male fertility associated with cancer treatments.
Among males unexposed to radiation, exposure to individual alkylators, including cyclophosphamide 3. This builds upon prior evidence for a dose-dependent increase in risk of infertility and impairment in spermatogenesis among male cancer survivors treated with alkylating chemotherapy — Compared with sibling control subjects, male childhood ALL survivors appear to have normal fertility, presumably due to low alkylator exposure Although early reports suggested that pubertal males are more susceptible to gonadotoxicity, the CCSS and St.
Although unilateral orchiectomy theoretically spares the unaffected testis, sperm concentration decreases post-procedure and azoospermia may occur among men who initially presented with oligospermia Retrograde ejaculation was previously a frequent complication of retroperitoneal lymph node dissection , , but is now uncommon with nerve-sparing techniques — Despite data suggesting that testicular cancer survivors are as likely to sire a pregnancy as age-matched control subjects , adjuvant therapy for testicular cancer affects fecundity in some patients.
No data regarding effects on spermatogenesis or fertility are available Most male HL survivors will have normal fertility following treatment. Within a case-control study, Over the past several years, therapy has shifted away from regimens heavy in alkylator exposure and towards ABVD.
The variability in risk between regimens is substantial. All men should be encouraged to bank sperm at diagnosis, but opportunities to bank may still exist in early survivorship or in a relapsed setting before re-initiating therapy.
Limited data are available on risks to fertility among men receiving chemotherapy for acute leukemias. Patients with AML and ALL have been grouped together, despite differences in treatments, including in use of alkylating agents.
It seems likely that some patients experience at least transient azoospermia, even if some retain or recover spermatogenesis Given the uncertainty, all male patients should be offered sperm banking before treatment, particularly given the effect of HCT on fertility.
Pregnancies have been identified in female partners of males on imatinib therapy for chronic myeloid leukemia, though data are insufficient to conclude whether imatinib is associated with congenital abnormalities in offspring of males The risk of age-related loss of fertility due to delayed conception is less statistically significant for males because interrupting treatment for conception may be more feasible for males than females as only a washout period before conception might be recommended, whereas females are recommended to also hold treatment through the duration of a pregnancy.
Conditioning chemotherapy and radiation frequently lead to severe impairment of male fertility. The birth rate among male HCT survivors is statistically significantly lower than the general population, though pregnancies following heavily gonadotoxic conditioning regimens such as BuCy or BEAM and TBI have been reported — , In a retrospective study of adult male HCT survivors with median follow-up of 7.
Despite very low pregnancy rates, risk appears to vary by exposures. Because no patient is at low risk, sperm banking should be recommended for all pubertal males before HCT.
The testes are sensitive to small radiation exposures, and the effect on spermatogenesis depends upon gonadal dose and radiation schedule The testes may be exposed to dose scatter in abdominal and pelvic radiation for rectal cancer, testicular cancer, and other malignancies.
Abdominal radiation following unilateral orchiectomy for testis cancer yielded exposure to the remaining testicle of 0. Among men treated with radiation 0. Radiation therapy for HL may be associated with testicular exposure of 0. Similarly, among men treated for rectal cancer, exposures under 1.
Male childhood cancer survivors who receive more than 7. Young cancer survivors face wide variation in fertility risk attributable to age at diagnosis, disease, and treatment. Nevertheless, there is a need for additional biomarkers to improve prediction of impaired fertility, with emerging data suggesting that measures of ovarian reserve such as AMH may add value.
Future studies will need to assess the risks of modern treatment regimens, including potential impact of targeted and immune-based therapies, and the role of ART on pregnancy rates in survivor populations. Recognizing the importance of survivorship issues, clinical trials should aim to incorporate patient-reported outcome measures to collect long-term fertility data.
Understanding what is known and what is unknown about fertility risks is needed in order to counsel patients optimally regarding situations in which fertility preservation strategies may be needed and when patients can feel confident foregoing them. Newly diagnosed young patients with cancer and survivors may also benefit from the development and incorporation of counseling tools and guidelines for referral to oncofertility specialists. National Center for Biotechnology Information , U. Published online Apr 9.
Author information Article notes Copyright and License information Disclaimer. Correspondence to: Ann H. Find out about when you might have it, how you have it and possible side effects. Hormone therapy blocks or lowers the amount of hormones in the body to stop or slow down the growth of cancer. Biological therapy is a type of drug treatment, it is sometimes called targeted treatment. There are a number of different types.
They are a treatment for some, but not all, types of cancer. About Cancer generously supported by Dangoor Education since Questions about cancer?
Call freephone 9 to 5 Monday to Friday or email us. Skip to main content. Home About cancer General cancer information Treatment for cancer Cancer drugs Side effects of cancer drugs Sex, fertility and cancer drugs. How cancer drugs can affect your sex life and fertility Doctors use many different types of drugs to treat cancer. Chemotherapy Some chemotherapy drugs can cause changes to fertility.
How much, will depend on: the type of drug, for example, some alkylating drugs like cyclophosphamide are more likely to cause infertility the total amount of the drug you have had over time cumulative dose Read about the effects of chemotherapy treatment on fertility. It is important not to become pregnant or father a child while taking any type of cancer drug.
The drugs may harm a baby developing in the womb. Look up your cancer drugs to see if they might affect sex and fertility. Read about early menopause due to chemotherapy. Read about the side effects of hormone therapies for women. Read about the side effects of hormone therapies for men.
Find out more about men's fertility and chemotherapy. Contact our cancer information nurses for more information on sex and fertility after cancer drug treatment on freephone The types and doses of chemotherapy drugs you get: We know that certain chemotherapy medicines are more likely than others to cause infertility, including Cytoxan chemical name: cyclophosphamide.
Platinol chemical name: cisplatin and Adriamycin chemical name: doxorubicin carry a medium risk of losing fertility. Few studies have been done on how these medicines may affect fertility and the results aren't clear yet.
Because research in this area is limited, it can be difficult to give an individual woman an accurate idea of her chances of keeping her fertility. It's a good idea to talk to your doctor, a fertility expert, or both about the potential risk of infertility with your chemotherapy treatment plan. Researchers are looking at ovarian suppression — stopping ovarian function using medicine — to help protect a woman's eggs during chemotherapy. But this is very controversial because there is limited information available.
Some doctors are concerned that the medicines used to suppress ovarian function, called GnRH gonadotropin-releasing hormone agonists, may interfere with chemotherapy's ability to kill cancer cells when the cells are actively growing.
GnRH agonists are hormones, and besides suppressing ovarian function, they may also stop or slow the growth of breast cancer cells. This would make the cancer cells less sensitive the chemotherapy.
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