by Drs. John Jain, MD, and C.H. Weaver MD, updated 11/2022
Hundreds of thousands of women in the United States are diagnosed with cancer each year. Many of these women are in their reproductive years and have not yet started or completed their families. Young women with cancer are increasingly surviving their disease because of improved treatment and earlier detection. While chemotherapy, a mainstay of cancer treatment, has decreased recurrences and improved survival, these medications also induce ovarian damage and aging, resulting in premature ovarian failure, infertility, and early menopause in cancer survivors.
Though the potential for infertility is known to be a great source of stress for female cancer survivors, it can get lost in the whirlwind of emotions as a young woman faces her diagnosis of cancer; and because timely initiation of chemotherapy is an essential element to improving survival, many times fertility concerns are placed on the back burner and addressed only after chemotherapy or other cancer treatments are completed. It is important to understand, however, that the best time for fertility preservation is clearly prior to initiating chemotherapy or radiation. Here are some reasons why.
Chemotherapy and radiation reduce egg quantity.
It is known that chemotherapy and radiation to the pelvis can dramatically reduce a woman’s supply of eggs. This can lead to premature menopause, and even those who resume or maintain regular menstrual cycles after chemotherapy may suffer infertility due to a reduced egg supply. Particularly at risk are women receiving higher doses of radiation and/or chemotherapy and certain types of chemotherapy (such as alkylating agents) and those who are older than 35 at the time of treatment. Because it is not possible to predict the impact that cancer therapy will have on an individual woman’s egg supply, it is important to consider preserving fertility while there are still adequate numbers of eggs remaining.
The effect of chemotherapy and radiation on egg quality is unknown.
The concept of a woman’s “egg quality” is derived from the observation that the probability of an embryo’s implanting is strongly related to the age of the woman who provides the egg and to her overall egg supply. Therefore “egg quality” is synonymous with “the probability of embryo implantation.” The quality of an egg cannot be determined by looking at it or its resulting embryo. Just because an embryo looks good in the laboratory does not mean that it will implant. The only proof of good egg quality is in the embryo actually implanting.
One way to think of diminished egg quality is “the battery theory of aging.” Consider each egg as possessing a number of batteries that provide its energy. The batteries represent tiny organs in all of our bodies’ cells called mitochondria, which provide the energy for our cells to function. As we grow older, the energy-producing capacity of the mitochondria decreases. The egg is packed with mitochondria because it requires huge amounts of energy to drive the processes of fertilization, embryo growth, and implantation. The older egg usually looks normal at the time of ovulation, and its initial fertilization and embryonic development remain normal. This is because its energy stores are still adequate. It soon runs out of batteries, however, and the embryo stops growing. Implantation is not achieved because the embryo stops growing before it reaches the implantation stage.
As women age, the quantity of eggs decreases and the quality of eggs declines along with it.
This is the reason why the probability of embryo implantation decreases as a woman ages. While it is known that chemotherapy and pelvic radiation can reduce egg quantity in women with cancer, the effect on egg quality remains largely unknown. Though some women do consider embryo or egg freezing after completion of their chemotherapy or radiation, and many of them do produce eggs and embryos to freeze, the quality of the eggs after exposure to cancer therapy is not known. Thus to avoid potential effects of cancer therapy on egg quality, the best time for fertility preservation is before the initiation of chemotherapy or radiation (particularly in the region of the pelvis).
Not all chemotherapy treatment will result in side effects that relate to your reproductive ability or sexuality, but some may. Reproductive problems are a frequent side effect of cancer treatment, especially chemotherapy. Patients may recover their ability to have children or this side effect may be permanent. Hormonal therapy may help some women overcome reproductive problems. For men, storing sperm before undergoing treatment should be considered in case reproductive function is permanently damaged. Sexual dysfunction is also common, but open communication with your partner and doctor as well as taking steps to improve your self-esteem can help.
What reproduction or sexuality side effects may occur?
It is perfectly natural for people who have been diagnosed with cancer to be concerned about the effect of their illness on their sexuality. Especially right after the diagnosis, you may temporarily lose interest in sex as you focus on understanding your cancer and the treatments available. During or after treatment, you may have difficulty accepting the way your body looks or functions and may have fears about your partner’s acceptance of the changes.
Changes in your reproductive abilities or sexuality due to cancer treatment may include:
- Gynecomastia (formation of breast tissue in men)
- Impotence (inability to achieve or sustain an erection)
- Irregular menstrual cycles
- Menopause, and related symptoms
- Reduced sexual desire
- Vaginal dryness
Some of these side effects will resolve after treatment is completed, while others may be more long term.
Which chemotherapy drugs cause reproductive problems?
All chemotherapy drugs can affect reproductive abilities; however, the class that is most commonly associated with reproductive problems are the alkylating agents, see table 1, as well as several other chemotherapy drugs.
Chemotherapy drugs that have been reported to cause reproductive problems in 10% or more of patients
- Busulfan (Busulfex®, Myleran®)
- Cyclophosphamide (Cytoxan®, Neosar®)
- Mechlorethamine (Mustargen®)
- Melphalan (Alkeran®)
- Procarbazine (Matulane®)
Other chemotherapy drugs
- Daunorubicin (Cerubidine®)
- Doxorubicin (Adriamycin®, Rubex®)
- Epirubicin (Ellence®)
- Etoposide (VePesid®, Toposar®, Etopophos®)
- Idarubicin (Idamycin®, Idamycin PFS®)
- Lomustine (CeeNU®)
- Methotrexate (Rheumatrex®, Trexall®)
Furthermore, a major cause of damage to the testes in men is treatment with platinum compounds:
- Cisplatin (Platinol®)
- Carboplatin (Paraplatin®)
- Oxaliplatin (Eloxatin®)
How is sexual dysfunction managed
Coping with sexual dysfunction may be very difficult. Maintaining open communication with your doctor and your partner, as well as taking steps to improve your self-esteem may help.
Communication: Without a doubt, one of the most common problems regarding cancer and sexuality is people’s reluctance to talk about it with their sexual partner and their healthcare team. However, communication is the key to coping with this difficult topic. Cancer care specialists are accustomed to addressing these issues every day.
Perhaps more importantly, sharing your thoughts, feelings, and any fears you may have regarding sexual dysfunction with your partner is essential to maintaining an intimate relationship with that person. Through open communication, you and your partner can work toward finding other ways to express yourselves beyond intercourse, such as gentle touching, holding hands, kissing, hugging and sharing emotional closeness.
Self-esteem and body image: Concerns about the impact of cancer and treatment on sexuality are often closely linked to issues of self-esteem and body image. Cancer treatment often involves surgery; surgery can leave scars and cause physical or neurological damage. Radiation treatment and chemotherapy can produce side effects such as hair loss and extreme fatigue. These effects and others can strongly influence how a person with cancer feels about his or her body and sexuality.
To support a positive self-image, follow these suggestions that have helped many people with cancer:
- It sounds simple, but looking better may actually help you feel better. Try to maintain the same grooming habits—fashion, hairstyle, and so on—as you did before your diagnosis.
- Plan special activities for both the days when you’re feeling well and those when you aren’t. Acknowledge that cancer and treatment can cause shifts in mood.
- Enjoy the days when you’re feeling well. On those days that are difficult, keep a positive outlook—plan all you’d like to do as soon as you feel better.
- If you need help with clothes and hair and other aspects of your appearance, don’t hesitate to ask for it. The “Look Good…Feel Better” program of the American Cancer Society (ACS), for example, can help.
- The ACS publications, “Sexuality for Women and Their Partners” and “Sexuality for Men and Their Partners” may be helpful to you.
What treatments are available for reproductive or sexuality issues?
In recent years, several drugs have been developed for men with erectile dysfunction. These drugs help men maintain an erection by inhibiting an enzyme. Examples include sildafenil (Viagara®), tadalafil (Cialis®) and vardenafil (Levitra®).
There are also medications available to help women deal with the symptoms of menopause. Make sure to tell your doctor what symptoms you are experiencing so that proper steps can be taken to provide some relief.
Fertility Preservation Options for Women
The standard fertility preservation method is embryo cryopreservation, though oocyte cryopreservation may also be considered. For either method the process is similar to that of in vitro fertilization (IVF) in that it involves ovarian stimulation with daily injectable hormones for approximately 10 to 14 days to achieve multiple eggs.
One of the key elements of achieving success with IVF, embryo freezing, or egg freezing is the ability to stimulate and retrieve multiple eggs. Based on decades of clinical experience with IVF and frozen embryos, it is clear that having multiple embryos to transfer increases the chance of future pregnancy. Because each individual embryo has only a relatively small chance of implanting, or “sticking,” in general the more embryos you have, the better.
Live birth rates from frozen-thawed embryos depend on the age of the woman at the time of the egg retrieval, ranging from approximately 30 to 40 percent per transfer for women younger than 35 years, to 10 to 20 percent per transfer for women between 41 and 42, assuming there are multiple embryos to transfer.
Data from women whose average age was 33 at the time of egg freezing suggest that approximately 5 percent of thawed eggs will successfully implant and 4 percent will result in a live birth. Thus approximately 20 to 25 eggs would need to be thawed to achieve a single live birth, and freezing 10 to 12 eggs would be expected to yield about a 50 percent cumulative chance of a live birth. One can assume that the older a woman is at the time of oocyte cryopreservation, the lower the probability of a live birth in the future.
Though some women do consider embryo or egg freezing after completion of their chemotherapy or radiation, the response to the ovarian stimulation is nearly always diminished, resulting in fewer eggs or embryos to freeze and a lower chance of pregnancy in the future. Thus to optimize the quantity of eggs produced and the chance of pregnancy, fertility preservation procedures are best done prior to initiation of chemotherapy or pelvic irradiation.
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Answers to Frequently Asked Questions
What type of cancer treatment can affect my fertility potential?
In particular, chemotherapy and/or radiation have become essential components of cancer treatment and are directly gonadotoxic, or injurious to ovaries. In addition, surgical removal of any of the reproductive organs may also have an impact on your fertility potential. For example, treatment for gynecological cancer may involve the removal of the uterus (hysterectomy), ovaries (bilateral oophorectomy), or some portion of the reproductive tract such as the cervix, vulva, or vagina. Some operations may involve these organs but spare reproductive function, although the scar tissue that develops after surgery can also hinder conception. The surgery that is performed will depend on the type of cancer and whether it has spread to other organs.
How might my ovaries be damaged by the surgeries or treatments described above?
The damage may be total, resulting in immediate ovarian failure; or your ovaries might be only partially damaged, resulting in early menopause and increased difficulty in achieving conception.
Why does chemotherapy affect my ovaries?
Your oocytes (eggs) are completely formed during fetal development and are stored in a “resting pool” in your ovaries. After birth these oocytes do not regenerate but rather decline with age. This depletion process actually begins before birth and proceeds throughout the reproductive years (approximately 12 to 40 years of age). Total depletion results in ovarian failure (menopause).Your oocytes naturally decline as you age. During this maturation phase, thousands of oocytes leave the resting pool at any given time; supporting cells surround each oocyte and divide rapidly to provide nourishment. Because chemotherapy targets tissues with actively dividing cells (such as the skin, hair, and digestive tract), the ovaries are also a potential target.
What kind of symptoms or side effects can I expect if there is injury to my ovaries?
Symptoms of ovarian failure include hot flashes, vaginal dryness, and the absence of menses. Alternatively, you may not experience any symptoms until you try to conceive.
If I am having menstrual cycles after treatment, does that mean my reproductive capacity has been spared?
Not necessarily. Evidence from population studies suggests that, as the number of oocytes diminishes, reproductive capabilities decline. Furthermore, current knowledge indicates that the inability to conceive usually precedes menopause by 10 years despite continued normal menstrual cycles. Therefore the presence of menstrual cycles does not ensure the ability to reproduce.
What is my risk of infertility?
It can be assumed that most chemotherapeutic agents have an adverse impact on the ovaries and may therefore compromise your reproductive lifespan compared with your baseline genetic potential. The effect of radiation is dependent on the dose and the field of exposure. Several studies have attempted to estimate the risk of ovarian dysfunction from radiation, but most of these focus on events surrounding the treatment period and lack long-term follow-up. The best estimates are that 5 to 35 percent of individuals will be able to conceive following chemotherapy, and fewer following radiation if the field includes the pelvis.
What factors influence the risk?
The risk of infertility following treatment depends on many factors, some of which include age at diagnosis, baseline ovarian reserve, type of cancer, chemotherapeutic/radiation regimen, type of surgery, and when you are planning to conceive.
Are there options that will preserve my chances of building a family?
Your options will depend on the type of cancer and the cancer treatment protocol. These options may include ovarian suppression and assisted reproductive technology (ART).
What is Assisted Reproductive Technology?
Assisted reproductive technology entails the retrieval of eggs and sperm for the purpose of reproduction. The gametes (spermatozoon and ovum)can be used for the creation of embryos that can then be transferred back into the uterus or cryopreserved (frozen) for later use. The procedures necessary to retrieve eggs include established methods such as ovarian stimulation, followed by an egg harvest, or experimental methods such as an ovarian tissue biopsy.
What is ovarian stimulation?
Ovarian stimulation is a process whereby we synchronize your cycle with a drug regimen to increase the number of viable mature eggs. Briefly, this entails subcutaneous hormone injections for approximately two weeks, followed by several ultrasounds to evaluate follicle (egg) development.
When is the best time to do ovarian stimulation?
The best time frame for the utilization of ART is before any chemotherapy or radiation has been administered. Following chemotherapy or radiation, the potential to retrieve eggs diminishes. In addition, there is animal evidence to suggest that if conception occurs within six months to one year of exposure to chemotherapy or radiation, there is a potential increase in fetal abnormalities.
How much time is needed to perform the procedures?
Two to six weeks are required.
How many eggs can you get?
It depends on your ovarian reserve and where you are in your menstrual cycle as well as on how much time you have available prior to your cancer treatment.
Should I stop my birth control pills prior to seeing an infertility specialist?
You should stop taking birth control pills only if you have a hormone receptor–positive cancer. Otherwise you should not stop taking them. The birth control pills will enable better coordination of your treatment.
When is the best time to see an infertility specialist?
You should see an infertility specialist as soon as your cancer has been diagnosed. The specialist will want to have a working relationship with your oncologist(s) to coordinate your treatment and minimize any delays in beginning your cancer therapy.
What if I don’t have a partner? Can I freeze my eggs?
Yes, you can have your eggs frozen, but the procedure is experimental. The reported success rate for a live birth after freezing eggs is 2 to 6 percent per oocyte retrieved. This is a viable option for young women with ample ovarian reserve. The average number of eggs retrieved for a 25-year-old is 20. This area is of great research interest, and advancements are continually being made, with corresponding improvements in pregnancy rates.
If I have already had treatment or I am unable to delay my treatment, what are my options?
If you cannot delay treatment, you might consider ovarian tissue freezing. During this procedure ovarian tissue is surgically removed and stored for later use. When ready, the tissue can either be transplanted back into the ovary or into another location in the body (such as the forearm). This procedure is experimental, and to date two patients have achieved pregnancy following transplantation. Other options depend on your type of cancer, treatment status, and ovarian reserve. If you are in remission and have an adequate ovarian reserve, you might attempt natural conception. In any event it is recommended that you see an infertility specialist early in the process if you have undergone cancer treatment and you want to conceive. If your ovarian reserve has been compromised but not eliminated, fertility treatments can be provided. If you no longer have an ovarian reserve, egg donation and adoption are options. Alternatively, if you are not ready to achieve pregnancy but desire to preserve your fertility, ovarian stimulation and egg harvest may still be possible at least six months to one year following cancer treatment. Success will depend on your ovarian reserve and the effects of your treatment.
Will ART procedures compromise my cure?
The answer to this question is not completely known, although current data suggest that ART procedures do not compromise cure rates or recurrence rates, even with hormone-responsive tumors.
Is my children’s cancer risk decreased if I utilize ART?
If you carry genes for hereditary cancers such as the breast cancer gene (BRCA), the utilization of ART with pre-implantation genetic diagnosis (PGD) may decrease the risk of transmission to your children. PGD involves the ovarian stimulation and in vitro fertilization process, followed by an embryo biopsy to identify and choose for transfer those embryos without the mutation.
If I have had chemotherapy and I am able to conceive naturally, is there an increased risk of fetal abnormalities?
The answer to this question is not completely known. The best available data suggest that if you wait at least six months to one year prior to conception, the incidence of fetal abnormalities will be no different than those in the general population.
Are there medical concerns if I get pregnant following cancer treatment?
This depends on the type of treatment. If abdominal or pelvic radiation has been administered, it could—depending on the dose—compromise your uterus and lead to miscarriage, low birth weight, or premature birth. If chemotherapy has been administered—again, depending on the regimen—it could compromise your heart and lung function. If there is no target organ damage, there is no additional risk.
Does my recurrence risk increase if I get pregnant?
The answer is not completely known. Current data suggest that if sufficient time has passed and you are in remission, there is no increased risk of recurrence regardless of your hormone receptor status.
If I am in menopause, can I still carry the pregnancy?
Yes. Hormone supplementation will be administered until the placenta has developed (at approximately eight weeks’ gestation). Once developed, the placenta will produce all the hormones necessary to maintain the pregnancy. If you are undergoing cancer treatment, you may already be aware that cancer therapies—including chemotherapy and radiation—can cause infertility and premature menopause. What you may not know is that resuming regular periods after completing your cancer treatment is not necessarily a sign that your fertility has been unaffected. Although many women will resume regular menstrual periods after treatment, this does not necessarily indicate that they are fertile. In fact, the presence or absence of menstruation is a highly inaccurate assessment of the potential for pregnancy.
What do regular periods indicate?
The good news about having menstrual periods is that, if you are menstruating at regular intervals of every 24 to 35 days, you are likely ovulating (releasing a mature egg) each month. The process of ovulation is a complex and tightly controlled sequence of events that is driven by hormonal signals from the hypothalamus and the pituitary gland in the brain. Most women stop having periods during their cancer treatment, possibly due to stress mechanisms that signal the brain that it is not a good time to have a baby. As the acute stress of cancer therapy comes to an end, the hormonal signals can recover and ovulation can resume. Although ovulation is a necessary component of conceiving, it is only the first step in a series of essential events that precede a successful pregnancy.
Infertility despite regular ovulation: how does it happen?
After ovulation, additional events that need to occur to achieve pregnancy include fertilization, embryo cell division, and implantation. These are primarily influenced by the egg; and, of a woman’s finite supply of eggs, only a fraction of them are able to accomplish these events with the necessary precision and efficiency—a concept we refer to as “egg quality. ”Women who have not been exposed to cancer therapies experience an accelerated decline in fertility at an average age of 37 due to reduction in the number of eggs and a corresponding loss of high-quality eggs. Within a matter of years, a critical threshold is reached at which the number of eggs and the quality of eggs is too low to result in a successful pregnancy. Thus cessation of fertility occurs at an average age of 41, though menstrual cycles continue to be regular and ovulatory until age 46, on average. Chemotherapy and radiation to the pelvis can dramatically reduce a woman’s egg supply, with higher doses leading to greater degrees of loss. As a result, many women have a shortened window of time to achieve pregnancy. If the remaining pool of eggs is below the critical threshold following cancer therapy, pregnancy using one’s own eggs is no longer possible regardless of whether menstrual cycles are occurring. The most reliable way to assess fertility after cancer therapy is through measurement of hormone levels in the blood (follicle-stimulating hormone and estradiol levels timed to specific phases of the menstrual cycle, and anti-Müllerian hormone levels). An ultrasound of the ovaries can also be useful to approximate fertility potential. These tests are best performed and interpreted by reproductive endocrinologists.
Some Final Thoughts
If you are considering having children after completing your cancer treatment, be sure to speak with your oncologist about your fertility questions before your treatment begins. The impact of cancer treatment on a woman’s fertility varies from individual to individual, so it is important to understand the risks that are specific to you. For many women, consulting a fertility specialist and/or undergoing a fertility preservation procedure prior to the initiation of cancer treatment is an excellent choice.
One Patient’s Journey
Fertility preservation treatment prior to chemotherapy or radiation remains the most effective way to safeguard future fertility for women facing a cancer diagnosis. For this reason a frank discussion of fertility preservation options should occur prior to cancer treatment. Here, Dr. John Jain discusses one option—cryopreservation—and one patient’s journey of hope.
When I first met with Susan,* a 33-year-old married woman, she had recently found a lump in her right breast and had been diagnosed with Stage I invasive breast cancer. Due to the small size of her breasts, she had undergone a right mastectomy and was set to begin adjuvant chemotherapy in six weeks. When Susan and I had our initial meeting, we discussed the fact that several important issues must be evaluated before any cancer patient could initiate a program of fertility preservation. These issues include the age of the patient as well as the stage and the type of the cancer. Fertility preservation options are best suited to women under 40, as this represents the most fertile period, when viable egg count is still sufficient. In Susan’s case I was able to tell her that she was a good candidate for cryopreservation (freezing of eggs or embryos) because of both her age and the fact that her Stage I diagnosis did not require immediate therapy, which would have precluded egg harvesting.
Though Susan and her husband were counseled on both egg and embryo cryopreservation, they ultimately decided to proceed with egg freezing because they had ethical concerns about the disposition of embryos should Susan not survive her cancer. Although egg freezing was still considered an investigational procedure, results indicated that it may be as effective as freezing embryos. As we discussed the couple’s options, I was clear about the fact that, generally speaking, in cases where either eggs or embryos are preserved, clear advance directives are imperative to avoid future conflict.
Having made the decision to move ahead with egg freezing, Susan began the process of ovarian stimulation. Typically, for egg or embryo cryopreservation, ovarian stimulation is initiated at the start of a menstrual period, although more-rapid methods can be utilized to accommodate cancer treatment schedules. Daily injections of medications are required for ovarian stimulation to induce multiple eggs. These medications are administered for approximately 10 days, followed by ultrasound-guided egg retrieval under anesthesia. The eggs can then be frozen or fertilized with sperm and frozen as embryos. An important factor that Susan had to consider as the couple moved forward was the fact that the daily injections she was required to undergo would cause elevated circulating levels of estrogen. This increased estrogen exposure is a particular concern for women with estrogen-sensitive cancers, such as breast cancer.
One method to lower this risk is to use an aromatase inhibitor, a drug that lowers the amount of estrogen produced. This method yields fewer eggs and embryos than traditional egg stimulation, however, and the ultimate effect of low estrogen production on egg and embryo quality has yet to be fully determined. The effect of one to two weeks of elevated estrogen on cancer risk is not known. Taking the risk of increased levels of estrogen into account, and considering Susan’s breast cancer characteristics, she and I discussed the option of an aromatase inhibitor protocol versus a traditional protocol.
Because the couple wanted to maximize the yield of eggs, they chose a traditional protocol, which was modified with the addition of an aromatase inhibitor administered after the eggs were removed. This worked to stop further production of estrogen. Given Susan’s good prognosis, her oncologist supported this approach. Ultimately, the cycle yielded 20 mature eggs for cryopreservation. Now, a year later, Susan and her husband have not yet attempted to conceive but feel very fortunate to have made the choice they did. Their decision provided them with a sense of hope and the ability to focus on Susan’s treatment at the time. And now, although Susan may very well conceive naturally, the couple feels that concerns about diminished egg counts and a possible increase in birth defects following cancer therapy make the frozen eggs they were able to secure a priceless gift.* This patient’s name has been changed to protect her privacy.