by Dr. C.H. Weaver M.D. updated 8/2020
Women treated in childhood for cancer and those diagnosed and treated as adults experience a high rate of infertility, however both groups can have children. Breast cancer is the number one cause of cancer in women of reproductive age and infertility can occur after cancer treatment with chemotherapy or radiation to the pelvis and the risk increases with age. At the time of their diagnosis, many women have not yet started or completed their families.
The risk of ovarian failure after cancer treatment also increases with the age of the woman at the time she is undergoing treatment, ranging widely from 35 percent in younger women to up to 90 percent in women over age 40. When a woman experiences ovarian failure or menopause, her egg supply is essentially depleted, and achieving pregnancy with her own eggs becomes highly unlikely if not impossible. This is considered “premature” if it occurs at or before the age of 40.
Questions about how cancer and treatment affect the ability to get pregnant in the future often arise as women face their diagnosis and begin cancer treatment. Some of the common questions and answers are discussed here.
Q: How does cancer therapy affect fertility?
Though the diagnosis of cancer itself is not believed to have an impact on a woman’s fertility, certain treatments for cancer do. Two common components of breast cancer treatment—chemotherapy and hormone therapy—are very effective in decreasing recurrences and improving survival, but these treatments may also negatively affect a woman’s future ability to conceive. It is known that chemotherapy, especially medications called alkylating agents (such as Cytoxan® [cyclophosphamide]), can immediately and dramatically reduce a woman’s supply of eggs. Because all women are born with a limited quantity of eggs, which naturally declines over the years until menopause (when the egg supply is essentially depleted), a reduction due to chemotherapy can result in premature menopause in 15 to 89 percent of patients.
Premature menopause can happen right away or may come a few years after a woman finishes treatment. Even in women who resume regular menstrual periods after treatment, there may be a shortened window of time to achieve pregnancy. If the remaining pool of eggs is already below a critical threshold immediately following cancer therapy, pregnancy using one’s own eggs may no longer be possible regardless of whether menstrual cycles are occurring. Unlike chemotherapy, hormone therapy is not known to directly damage the ovaries or affect the egg supply. Because the duration of treatment is typically 5-10 years, however, many women will experience age-related infertility by the time they complete their tamoxifen. Throughout a woman’s reproductive years, there is a gradual and natural reduction in the number of eggs and a corresponding decrease in the quality of eggs. Women generally experience an accelerated decline in fertility at an average age of 37. Within a matter of years, a critical threshold is reached at which the number and the quality of eggs are too low to result in a successful pregnancy. Thus cessation of fertility naturally occurs at an average age of 41 to 45, though menstrual cycles continue to be regular until about age 46 to 50. For women who start tamoxifen after the age of 35, there is a substantial risk of age-related infertility by the time they complete a five-year course.Because it is difficult to predict whether a woman will be fertile after cancer treatment, it is a good idea to consider fertility preservation options before starting treatment for those who would like to have children in the future.
Q: What are the options for fertility preservation before treatment?
In vitro fertilization and freezing embryos (fertilized eggs) is the most proven method of fertility preservation; it is the ideal option for women who are married, have a male partner, or are interested in using donor sperm. Women who are single and are not interested in using donor sperm can consider freezing eggs. Whether freezing eggs or embryos, the process starts with the beginning of a menstrual period and takes about two weeks to complete. For that reason these methods are most suitable for women who can safely delay cancer treatment for two to six weeks. For women who need to start chemotherapy immediately, ovarian tissue can be removed surgically and frozen for future use.
Q: How do I know whether I am fertile after cancer treatment?
Many women will resume regular menstrual periods after treatment, but this does not necessarily mean that they are fertile. The most reliable way to assess fertility after cancer therapy is by measuring hormone levels in the blood (follicle-stimulating hormone, estradiol and progesterone 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.
Q: What are the options if I am not fertile after cancer treatment?
For women who are having trouble conceiving or are determined to have reduced fertility after cancer treatment, standard methods of infertility treatment such as in vitro fertilization can often help. For women who are menopausal after cancer treatment, donor eggs can be used and are very successful in achieving pregnancy.
Q: What are the options if carrying a pregnancy is not felt to be safe after cancer treatment?
So far research does not suggest that pregnancy after breast cancer triggers recurrence or decreases survival. Because of the known association between breast cancer and hormones like estrogen, which are elevated throughout pregnancy, however, some breast cancer survivors may be advised to avoid becoming pregnant. In those women for whom carrying a pregnancy is not felt to be safe, “gestational surrogacy” is an option. This refers to a treatment process in which embryos from the survivor are placed into the uterus of another woman—the gestational surrogate—who then carries the pregnancy to term. Adoption is also an excellent option.If you are considering having children after completing cancer treatment, be sure to speak with your oncologist about your fertility questions. Because the impact of breast cancer treatment on a woman’s fertility varies from individual to individual, 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 worthwhile.
Childhood cancer and Infertility
We have known for a long time that individuals who had childhood cancer may have limited fertility as a result of treatment. For boys, cancer therapy may lower sperm count. For girls it’s more complicated. They need functioning ovaries and a functioning uterus. They need their hormonal paths to induce menstrual cycles. All these functions can be adversely affected by treatments for childhood cancer. For example, many types of childhood cancer require radiation therapy. Radiation to the pelvic area might affect the ability of the uterus to grow during pregnancy, or it might affect the ability of the ovaries to produce eggs. Radiation to the brain can affect hormones produced there that tell the ovaries to cycle.
Q: What do we know about the likelihood that a woman who had cancer as a girl will be able to get pregnant? How does this compare with other women?
A: Research from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center as well as from Brigham and Women’s Hospital gives us valuable information about the fertility of women who were treated for childhood cancer, went through puberty normally, and are menstruating like any other woman. What we wanted to find out was *What are the chances that these women will get pregnant?*We looked at women of childbearing age, in their twenties and thirties, who had a history of childhood cancer. To find the women whose ovaries were not functioning normally, we asked if they were in menopause. If they were not in menopause, we asked whether they had ever tried to get pregnant for 12 months without success. Approximately 16 percent overall had some form of infertility, compared with about 11 percent in a control group composed of sisters of cancer survivors. This translates to roughly a 50 percent higher risk of infertility among women who had been treated for childhood cancer.About 3 percent of the cancer survivors were in menopause. About 13 percent were menstruating and appeared to have functioning reproductive systems but had not conceived after trying for a year. About two-thirds of these menstruating women eventually got pregnant. That is roughly the same rate of eventual conception found among all women who have tried unsuccessfully for one year to get pregnant. This tells us that women who survived childhood cancer have a good chance of getting pregnant, even though it might take them longer.
Q: Are certain women who were treated for childhood cancer at particular risk of infertility?
A: Women who had been treated with alkylating agent chemotherapy (drugs like cyclophosphamide and nitrogen mustard) or who received radiation to the abdomen or pelvis were most likely to experience infertility. They were more likely to experience early menopause and clinical infertility and not get pregnant at all following clinical infertility.The biggest risk of infertility for any woman, whether she has had childhood cancer or not, is older age. Fertility rapidly declines after age 35. This was true among the cancer survivors as well. In fact, they didn’t look all that different from their siblings when they entered their late thirties. It was really at the younger ages that we saw a significantly elevated risk of infertility among the women who had been treated for cancer as girls, compared with women who had not had childhood cancer.
Q: What advice do you have for women who had childhood cancer and want to get pregnant?
A: Physicians generally advise women to see a fertility specialist after trying to get pregnant unsuccessfully for a year. With women who were treated for childhood cancer, we recommend that they see a fertility specialist after six months. If you have irregular menses, received pelvic or abdominal radiation or alkylating agents, or are not sure of your treatment or fertility status, you may want to seek a specialist’s guidance as soon as you are ready to start trying to conceive. In addition, a 20-something young woman who had alkylating agents or radiation may want to have children at some point in the future but is not yet ready to conceive. She should make an appointment with a reproductive specialist to get information about egg preservation.
Q: What advice about fertility preservation do you have for parents whose child is diagnosed with cancer?
A: It is often very hard for a parent to deal with a new diagnosis of cancer in a young child and at the same time imagine a future when the child’s fertility becomes an issue. It is important to talk with a professional about various options so that you have the information you need to make a decision about fertility preservation. With postpubertal boys it is worth collecting their sperm because it is so easy. For adolescent girls it’s more complicated. Preserving eggs can delay cancer therapy for one to two weeks. It involves taking hormones and a minor procedure to harvest the eggs. It is more invasive than collecting sperm, so we reserve it for adolescent girls who are receiving therapies that we suspect will limit ovarian function. In addition, if a girl is being treated with radiation, we can sometimes move the ovaries away from the area where the radiation is being delivered.Whether it is a newly diagnosed child or a young woman who survived childhood cancer, parents and patients alike are best served by asking questions to help them make decisions about fertility and fertility preservation. Likewise it is important for caregivers to provide patients and parents with the information they need to make those decisions. Our research strengthens clinicians’ ability to do so by filling in some gaps in our understanding of the complex relationship between childhood cancer and fertility.
Egg Supply Testing after Cancer Treatment
The most reliable way to assess fertility after cancer therapy is to measure hormone levels in the blood, typically timed to specific phases of the menstrual cycle. An ultrasound of the ovaries can also be useful to approximate fertility potential. These tests are best performed and interpreted by a reproductive endocrinologist.
Basal (Day 3) Follicle-stimulating Hormone
Every woman is born with a set supply of eggs. Each egg is contained within a structure called a follicle, which is composed of layers of ovarian cells surrounding fluid that provides nutrients for the egg. Follicle-stimulating hormone (FSH) is produced by the pituitary gland in the brain, and its purpose is to stimulate follicles to grow. At the beginning of a menstrual period, FSH acts as the signal to the ovaries that it is time to prepare eggs for ovulation. One of the earliest indications that the ovarian reserve (the number of remaining eggs) is becoming critically low is an increase in FSH levels at the beginning of a menstrual period. FSH production increases as though it is trying to compensate for the tiring ovaries. For this reason, measurement of FSH in the blood is commonly used as a test of fertility.
It is important that this test be performed on or very near the third day of the menstrual cycle to be informative, and the test should be measured in conjunction with the estrogen level to ensure accurate interpretation. Higher day 3 FSH values correspond to reduced fertility. Normal values are different, depending on where your blood is drawn, but in general values above 10 to 15 international units per liter (IU/L) are considered abnormal. It is expected that the values will fluctuate from month to month, but even with one elevated test result, the chances of becoming pregnant are much lower.
Clomid Challenge Test
Because the basal FSH level will not detect every occurrence of a diminishing egg supply, the Clomid® (clomiphene citrate) challenge test can be used to unmask the problem. Clomid is a pill that is taken for five days starting on the fifth day of the menstrual cycle. FSH levels are measured on day 3 and day 10. In women with a normal supply of eggs, the FSH levels will be low on day 3 and day 10 after the five days of Clomid are completed. If either value is high (greater than 10 to 15 IU/L), the test result is considered abnormal.
Antral Follicle Count
Follicles can be seen and counted during a vaginal ultrasound examination in the early part of a menstrual period (on or around day 3). These follicles are thought to represent the ones that are getting ready to grow during that menstrual cycle. They also reflect the total number of follicles left inside the ovary. There are no well-established cutoff values for normal and abnormal, however, and the expected count definitely varies depending on a woman’s age. In general, the more antral follicles there are, the more plentiful the total egg supply is likely to be. For a woman under 40, 10 or more on each side is promising. For a woman who is 40 or older, six or more on each side is a good sign.
Using vaginal ultrasound, three diameters of each ovary (length, width, and height) can be measured in the early part of the menstrual period (on or around day 3), and total ovarian volume can be calculated. In general, ovarian volume is known to decrease with age and has been used to approximate ovarian reserve. Ovarian volume of less than 3 centimeters cubed (3 cm3) per ovary has been reported to indicate severely reduced ovarian reserve and very low likelihood of pregnancy.
Inhibin B and Anti-Müllerian Hormones
Inhibin B (ONHB) and anti-Müllerian hormone (AMH) are produced by the cells in the ovary that make up the outer layers of follicles. When these hormone levels are low, it suggests that the number of remaining follicles is low. Like FSH, inhibin B should be measured on or around day 3 of the menstrual period. AMH levels, however, do not vary throughout the menstrual cycle and can therefore be measured at any time. ONHB levels of less than 50 picograms per milliliter (pg/mL) and AMH levels less than 0.2 micrograms per liter (mcg/L) have been proposed to indicate severely diminished ovarian reserve. While these are very promising tests for fertility and ovarian reserve, they are not available everywhere, and doctors have not yet agreed upon the best way to interpret their results.
If you are interested in having children after completing cancer treatment, you should consider consulting a fertility specialist and having your ovarian reserve evaluated. Because the impact of cancer treatment on a woman’s fertility varies from individual to individual, it is helpful to be informed about your current fertility status before you begin trying to conceive.
Understanding Donor Egg IVF
An effective way to overcome infertility due to depletion of the egg supply is through the use of donor eggs. Egg donation is a type of fertility treatment that allows women who have no eggs of their own, or who have eggs of poor quality, to achieve pregnancy successfully. Because of this technology, tens of thousands of infertile and menopausal women in their forties and fifties have been able to give birth to healthy babies since the first birth from egg donation was reported in 1984. In the United States alone, well over 15,000 cycles of in vitro fertilization (IVF) using donor eggs are performed each year. At the present time, it is most often used for women who fail to become pregnant after multiple cycles of IVF using their own eggs, for those with premature ovarian failure or elevated levels of follicle-stimulating hormone (FSH), and for those beyond the age of 43. Interestingly, women in their fifties are nearly just as likely to have good outcomes from donor egg IVF as women in their thirties and forties.
The basic principle of egg donation is that it is an IVF cycle for two—the egg donor and the recipient (also referred to as the intended parent). Thedonor undergoes the first part of IVF, including ovarian stimulation and egg retrieval. The eggs are fertilized with the recipient’s male partner’s sperm (or donor sperm), and therecipient undergoes the embryo transfer, carries the pregnancy, and gives birth. Egg donors may be anonymous donors who are unrelated to the recipients and who donate for altruistic and/or monetary reasons. Anonymous donors are often found through donor agencies (organizations that focus efforts on recruiting and screening potential egg donors) or through the fertility clinic where the recipient is receiving treatment. Alternatively, the donors may be designated donors such as a friend or relative identified by the recipient to serve as a donor specifically to help her.
The egg donor is required to undergo a thorough medical examination, which includes a pelvic exam, an ultrasound to examine her ovaries and uterus, and a blood draw to check hormone levels, to test for infectious diseases, and to screen for certain genetic disorders. In addition, she will be evaluated by a psychologist, who will determine whether she is mentally suitable to complete the donation process. Prior to initiating the egg donation cycle, the donor signs legal contracts that waive her rights of ownership and custody to all resulting eggs, embryos, and offspring.
Once the screening is complete and the legal contracts are signed, the egg donor will begin the donation cycle, which typically takes three to six weeks. The key is to synchronize the recipient’s cycle with the donor’s cycle. This is achieved by a combination of birth control pills and a medication called lupron (which prevents ovulation and quiets a woman’s hormones). Once the women’s cycles are synchronized, the donor receives hormone injections to stimulate the growth of multiple eggs (typically 10 to 15), while the recipient takes a combination of estrogen and progesterone to prepare the uterine lining for the implantation. When the donor’s eggs are mature, she undergoes egg retrieval, a minor surgical procedure done under conscious sedation. The recipient’s partner provides the sperm, and fertilization takes place in the laboratory as with standard IVF.
Embryo transfer is the procedure by which embryo(s) are placed into the recipient’s uterus. It is usually scheduled for five days after the egg retrieval. After the embryo transfer is completed, the recipient continues to take estrogen and progesterone through the end of the first trimester of pregnancy. This is because in natural conception the ovaries produce these hormones to support the implantation. At the end of the first trimester (13 weeks of gestation age or about 10 weeks after embryo transfer), the placenta makes all the hormones that are needed, and estrogen and progesterone supplementation is stopped. Across the nation egg donor cycles are very successful, with an estimated 60 to 70 percent chance of pregnancy. If excess embryos are frozen for future use, when a “fresh cycle” is followed by a “frozen cycle,” the success rate with donor eggs goes up to approximately 80 percent. Multiple births, particularly twins, is a common outcome, and the risk of multiples depends on how many embryos are transferred. At the present time, the American Society for Reproductive Medicine recommends that no more than one or two embryos are transferred in any given donor egg cycle. Any remaining embryos are typically frozen for future transfers.
Egg donation is clearly the most successful fertility procedure available today, and it can be a wonderful option for women who are menopausal after cancer treatment. Women who are infertile or in menopause can successfully carry a pregnancy using eggs from an anonymous or known donor. In women with male partners, donor eggs can be fertilized with the partner’s sperm to create embryos that are genetically related to the father. For women without a partner or women in same-sex relationships, donor eggs can be fertilized with donor sperm, and some of these couples may elect to have the cancer survivor’s female partner serve as the egg donor. Donor egg IVF is not ideal for all cancer survivors, however, particularly women who have been advised not to carry a pregnancy for reasons related to their type of cancer (such as some breast cancer survivors) or to their medical conditions (women who have heart problems as a consequence of their chemotherapy). For these reasons it is important that you discuss all fertility questions with both your oncologist and a fertility specialist.