Female Fertility and Cancer Treatment
How does cancer therapy affect fertility?
Fertility is the ability to become pregnant and have a child. When a female is born, her ovaries hold hundreds of thousands of eggs. Starting at the end of puberty until menopause about 15-20 immature eggs (oocytes) are released every month. One of these will fully develop and become a mature oocyte. This mature oocyte is released into the fallopian tube. The egg is then either fertilized by sperm which leads to pregnancy or a woman will get her period (menstruate).
As a woman ages, the number of oocytes decreases. Over a lifetime, about 400-500 mature oocytes are released into the fallopian tubes. The undeveloped oocytes or the follicles needed to develop them can be damaged by cancer treatment. This can cause a woman's period to change or stop and can lead to infertility (inability to get pregnant). Damage to the uterus or cervix by radiation or surgery can affect a woman’s ability to carry a pregnancy to term. This article explains how different cancer therapies can affect fertility in a woman.
Chemotherapy and Fertility
Chemotherapy works by killing quickly dividing cells. Many cells in our bodies divide quickly, like those lining the gut, hair follicles, and germ cells (including sperm and oocytes or eggs). Both cancerous and non cancerous cells can be affected by chemotherapy. When these cells are damaged by chemotherapy, it causes side effects. These include diarrhea, mouth sores, hair loss, and the inability to have children.
There is no good way of knowing which women treated for cancer will become infertile (unable to have child). The risk is related to the medication(s) used, the dose that is given, how long it is given for, and the woman's age at the time it was given. Rarely does a person get only one chemotherapy agent. Receiving multiple medications makes predicting fertility even harder. Higher doses and longer treatments cause the highest risk of infertility. The older a woman is at the time of the treatment, the more likely it is that her periods will stop and/or she will become infertile.
Loss of fertility also depends on the size of the follicle pool (or number of oocytes) before chemotherapy. Given that this number lowers with age, the older the woman, the higher the risk of infertility becomes, because there are less oocytes to begin with. There is no way to know for certain how many oocytes a woman has at any point in life, but some tests can estimate this number. Age can act as a guideline, but it is not an exact science. (See assessment of ovarian function below).
Many studies look at when the menstrual cycle restarts as a predictor of fertility. Pregnancy can not happen without the return of a woman's period. But, the return of periods does not necessarily mean you can get pregnant. Women who get their period back after therapy are still at risk of starting menopause earlier than women who did not have chemotherapy or radiation.
With all of this in mind, we know that the group of chemotherapy agents called alkylating agents poses the greatest risk of causing infertility. These include cyclophosphamide, ifosfamide, BCNU, CCNU, chlorambucil, melphalan, bendamustine and busulfan. Bevacizumab, a type of targeted therapy, has been found to cause ovarian failure that in some cases is permanent. Little is known about other targeted therapies. Thalidomide and lenalidomide are examples of medications that can cause birth defects, so women are taught to use two forms of birth control while on these. Ask your provider about the possible effects on fertility and risk for birth defects related to the medications you are receiving.
Treatments used to prepare for stem cell and bone marrow transplant are likely to cause infertility in women. Transplant regimens using busulfan and/or cyclophosphamide are more toxic to a woman's fertility than those using melphalan. Studies have found that girls treated for childhood cancers before puberty have a good chance of regaining ovarian function.
There is not enough research on newer medications to know how they will affect fertility. If you are getting or have received chemotherapy, it is important to speak to your provider about when it is safe for you to try to become pregnant. Each therapy can affect you differently so it is important to talk openly with your team about your plans for having children in the future.
Radiation Therapy and Fertility
Damage to fertility caused by radiation therapy is dependent on the dose received, part of the body treated, and the woman's age at time of treatment. As with chemotherapy, the size of the follicle pool before treatment is directly linked to the number of oocytes remaining after therapy. Younger women are more likely to have a larger pool and therefore are less likely to enter permanent menopause at the time of therapy.
Younger women who regain periods (menses) after radiation therapy are at risk of starting menopause earlier than women who did not have radiation or chemotherapy. Predicting when this menopause will happen is hard, putting pressure on younger women who wish to have a natural pregnancy. As with chemotherapy, women who start to have their periods after treatment are not necessarily able to get pregnant.
Total body irradiation (TBI) is a technique used for stem cell and bone marrow transplants in which the whole body is irradiated. This treatment has been found to have a profound effect on fertility in women, leading to permanent ovarian failure in many of these patients. Girls who have received TBI before puberty are more likely to get back ovarian function than those who received it post-puberty.
Radiation therapy to the belly or pelvis can cause harm to the uterus and/or cervix. This can make it hard to carry a pregnancy to term. Studies have found that radiation can cause changes to the muscles, blood flow, and size of the uterus. This may keep an embryo from implanting. Women who received radiation to the uterus are at higher risk for miscarriage, preterm labor, and low birth weight babies. Despite these risks, the risk of birth defects is not increased, so long as radiation is not given during pregnancy.
The pituitary gland, located in the brain, makes hormones (LH and FSH) that stimulate the ovary to make and release a mature female oocyte. Radiation therapy to the brain can harm the pituitary gland, affecting the ovulation cycle. This can then result in a shorter luteal phase (days after ovulation during which fertilization occurs). This can often be fixed by taking supplemental hormones.
Surgery and Fertility
Surgery that removes both ovaries or the uterus, cervix, and/or fallopian tubes will affect fertility. Depending on how advanced the cancer is, some women may be eligible for fertility-preserving surgeries and should discuss these choices with their surgeon.
Tamoxifen can temporarily stop or alter menstruation, but this does not happen in all women. It is possible to become pregnant while on tamoxifen, so women should use two forms of birth control to prevent this. If a woman becomes pregnant while on tamoxifen, the medicine should be stopped right away due to the risk to the fetus. Also, tamoxifen can alter estradiol and FSH levels, making it hard to assess ovarian function in women on the medicine (see assessment of ovarian function below).
Assessment of Ovarian Function after Therapy
Fertility experts know that the return of a woman’s period is not a good predictor of fertility. There are a few tests that can help assess fertility. Follicle stimulating hormone (FSH) and estradiol (E 2) are hormone levels, which can be checked by a blood test on the 3rd day of menstruation. These levels are used to assess ovarian follicle reserve (number of eggs remaining in the ovary) and fertility.
These levels cannot predict exactly how many follicles are left or how long before infertility will start. One hormone, anti-Mullerian hormone (AMH), is made by early follicles and is a good predictor of the follicle reserve. Using ultrasound to count the number of antral follicles (those oocytes that are growing) on the 3rd day of the menstrual cycle can also be a good marker of follicle reserve. The fraction of follicles maturing is proportionate to the number that remain. While tamoxifen affects the levels of FSH and E 2, it does not affect the antral follicle count, so this test may be useful in predicting future fertility in women taking tamoxifen.
If a woman still ovulates, is there any danger or risk to becoming pregnant after therapy?
The concern of possible birth defects caused by exposure of oocytes to cancer therapies is a common one. Studies have found no increase in birth defects in the children of cancer survivors, nor do these children have higher rates of cancer themselves (this does not apply to families with genetic cancer syndromes).
The DNA of oocytes can be harmed by cancer therapies, but this damage can repair itself in the months after treatment (the exact time to repair is unknown). It may be suggested that you wait a certain amount of time after treatment before trying to get pregnant. Each woman should discuss her case with her oncology team and may benefit from speaking with a fertility expert who works with cancer patients.
For breast cancer survivors, there has always been concern that pregnancy after treatment could increase the risk of recurrence, particularly in estrogen receptor-positive tumors. However, studies have found that pregnancy does not appear to increase the risk of recurrence. Studies have not tested if it is safe for breast cancer survivors to take fertility medications if they are not able to get pregnant naturally.
It can be difficult, but it is important to speak openly with your care team about your fertility. You can also ask to be referred to a fertility specialist. You can also learn more about fertility preservation options and find links to resources for more information.
American Cancer Society. How Cancer Treatment Can Affect Fertility in Women. 2017. Found at: https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/fertility-and-sexual-side-effects/fertility-and-women-with-cancer/how-cancer-treatments-affect-fertility.html
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