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 house 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 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 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. These can be cancer cells or normal cells. Many cells in our bodies are quickly dividing, like those lining the gut, hair follicles, and germ cells (including sperm and oocytes or eggs). When these cells are damaged by chemotherapy, it causes side effects. These include diarrhea, mouth sores, hair loss, and the ability to have children.
It is often impossible to predict which women will become infertile as a result of cancer treatment. The risk is related 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 an even greater challenge. Higher doses and longer duration of treatment 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. As a woman ages, smaller doses of chemotherapy can result in infertility.
Fertility loss is also dependent 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 at the outset. Unfortunately, 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 the resumption of the menstrual cycle as a predictor of fertility. Pregnancy can not happen without the return of menses. Menstruation alone does not mean you can get pregnant. Some studies have reported pregnancy rates in survivors, but it is difficult to know how many were trying to get pregnant. One must also think about other variables like how often a woman is having unprotected sex, if her partner has fertility issues, cancer therapies received, and time since therapy. Women who do get back menses 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. These include cyclophosphamide, ifosfamide, BCNU, CCNU, chlorambucil, melphalan, bendamustine and busulfan. Some agents known to have a low risk of infertility are vincristine, methotrexate, and fluorouracil (5-FU). Bevacizumab, a type of targeted therapy has been found to cause ovarian failure that in some cases is permanent. Little is know 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.
Therapies used in preparation for stem cell and bone marrow transplant are likely to cause infertility in women. However, studies have found that pre-pubescent girls treated for childhood cancers have a good chance of regaining ovarian function. Transplant regimens using busulfan and/or cyclophosphamide are more toxic to a woman's fertility than those using melphalan.
There is not enough data on newer agents, such as taxanes and the many targeted therapies, to address fertility after these agents. 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. A dose of only 5 or 6 Gy can cause ovarian failure in a woman over 40, but larger doses (20Gy) are required to cause failure in women under 35. In women who received 20-30 Gy of radiation to the belly as children, 97% experienced ovarian failure or started menopause earlier than normal (average age at menopause was 23 years in these survivors). As a reference, 50 Gy is most often used in the treatment of common gynecologic cancers.
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 are not neccessarily 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, leading to trouble carrying 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 are 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 in some way. 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 a woman’s periods returning is not a good predictor of fertility. Although there is no foolproof predictor, 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. In a menstruating woman, an FSH above 12mIU or an E 2 level above 75pg/ml suggests severely impaired 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 repairs itself by six months after treatment (the exact time to repair is unknown). For this reason, and to get beyond the highest risk of recurrence, women are counseled to wait 2 years after therapy before becoming 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.
Options for Fertility Preservation
The majority of techniques need time, resulting in delays in treatment, which may not be possible for many women. For women without a partner or a desire to use donor sperm, the techniques are less reliable. Let's review the options used and those being developed.
Egg or Embryo Cryopreservation
Cryopreservation (freezing) of eggs or embryos uses the same collection process, which can take 2-4 weeks. Fertility-stimulating medicines are given in order to allow the release and collection of many mature oocytes.
For embryo cryopreservation, the egg must be fertilized with sperm. This presents a problem for women without a partner or willing donor. Donor sperm can be used, but not all women want to do this. This technique has a pregnancy rate of 20-25% once the embryo is thawed and implanted. There are costs for the stimulation and collection of the eggs, fertilization, storage, thawing, and implanting in the future. Insurance companies may cover some of these, but the laws vary by state.
Cryopreservation of eggs does not need sperm because these eggs are frozen unfertilized. Unfertilized eggs are more sensitive to the freezing process because they contain water that can form ice crystals and cause damage. A method of freezing called vitrification has made the process more successful in recent years. Some centers report the same success rates with egg freezing as with embryo freezing. As with embryo freezing, there are costs for the stimulation, collection, egg freezing, storage and ultimately fertilizing and implanting them in the future. Talk to your insurance company to see if any of the costs are covered.
Oophoropexy (Ovarian Transposition)
This method can be used to lessen the ovaries' exposure if pelvic radiation is needed. Often, one ovary is surgically moved to another area, out of the radiation field. This is often done along with a therapeutic surgery for the cancer, but can be performed laparoscopically for women who do not need other surgery. Women have been able to conceive after this procedure, but in some cases a second procedure is needed to return the ovary to its normal location, particularly when in-vitro fertilization is needed. The cost for oophoropexy can vary, but if it is done during a cancer surgery, there may be very little cost tied to it.
Ovarian Tissue Freezing
One advantage for this technique is that it may be a choice for young girls who have not reached puberty before cancer treatment. Using a laparoscopic technique, all or part of one ovary is taken out before the start of therapy. The outer surface of the ovary contains the eggs, and it is this area that is frozen for future use.
There are several ways to use this tissue. Ovarian tissue can be implanted back into the woman (called auto-transplant), either orthotopically (in the same location it was taken from) or heterotopically (in a different location, for example, the forearm). After implantation, the tissue matures and oocytes can be collected and used through in-vitro fertilization procedures.
A number of pregnancies have come from using frozen tissue, but this technique is still relatively new. It is not an option for some types of cancer, including leukemias, due to the risk of the cancer being present in the tissue. Many fertility clinics offer ovarian tissue freezing, but woman should investigate the cost and understand the limited experience with this technique.
Radical Trachelectomy & Conservative Surgery
Radical trachelectomy is a procedure used in the treatment of cervical cancer, as an alternative to the more standard surgical treatment of hysterectomy. Trachelectomy removes the cervix but leaves the uterus intact, and is best used for early stage cancers (stages IA and IB). These women will need cerclage (a technique to stitch the uterus closed to prevent premature birth or miscarriage). There is still a risk of premature deliveries or late miscarriages, and women may need IVF because of trouble getting pregnant due to the lack of a cervix. These pregnancies are thought to be high-risk, and will need a C-section for delivery due to the cerclage and the lack of a cervix. No randomized studies exist, but recurrence rates appear to be similar in women who have undergone hysterectomy.
Another conservative surgical approach for cervical cancer is cone excision, which removes only a part of the cervix. This is only used in very early stage cases.
For very early stage endometrial cancers, D&C may be sufficient, but these cases need careful examination and an experienced surgeon for successful results. In some cases, hormone therapy can be used to treat early stage endometrial cancers. This can allow a woman to keep her uterus and possibly carry a pregnancy in the future.
In cases of ovarian cancer limited to one ovary, it may be possible to keep the healthy ovary and uterus. Studies have reported survival rates similar to those treated with more radical surgery. These choices are clearly limited to early stage disease, but may be a choice for women with early stage disease wanting to preserve fertility.
One other method that has been tested is known as gonadoprotection or ovarian suppression. This works on the theory that the cells in the ovaries are harmed by chemotherapy because they are quickly dividing and reproducing. By giving medication temporarily shut down the ovaries, they might be protected from the damage of chemotherapy. This can be done with long-acting hormone medications called gonadotropin-releasing hormone (GnRH) agonists. This method may help maintain fertility for some women, but the research has not found it to improve pregnancy rates. This treatment is considered experimental at this time. It may be used when other options are not available in the hopes of reducing the risk of infertility
Fertility-preserving techniques for women can come at a major cost. Many patients will not have coverage for fertility-sparing procedures through their health insurance. The National Infertility Association has a website that includes up-to-date information on each state's laws. Women should talk to their insurance companies or human resource representatives to explore what is covered.
We have a long way to go in helping women facing cancer therapy to preserve their fertility. The future may see advances in tissue cryopreservation or new techniques to protect the ovaries and gynecologic organs from the damage of current therapies. A first step is making sure women know the options available to them, which unfortunately does not always happen.
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
Devita Jr, V. T., Lawrence, T. S., & Rosenberg, S. A. (2015). DeVita, Hellman, and Rosenberg's cancer: principles & practice of oncology. Lippincott Williams & Wilkins.
Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. Journal of Clinical Oncology 24:2917-31, 2006.
Leitao, MM & DS Chi: Fertility-sparing options for patients with gynecologic malignancies. The Oncologist 10:613-622, 2005.
Nieman CL, Kazer R, Brannigan RE, et al: Cancer survivors and infertility: a review of a new problem and novel answers. Journal of Supportive Oncology 4:171-8, 2006.
Oktay, K., Harvey, B. E., Partridge, A. H., Quinn, G. P., Reinecke, J., Taylor, H. S., ... & Loren, A. W. (2018). Fertility preservation in patients with cancer: ASCO clinical practice guideline update. Journal of Clinical Oncology, JCO-2018.
Save My Fertility. Found at: https://www.savemyfertility.org/
Schover L. State-of-the-art: parenthood after chemotherapy. Program and abstracts of the American Urological Association 2006 Annual Meeting; May 20-25, 2006 ; Atlanta, Georgia. Plenary Session II.
Simon B, Lee SJ, Partridge AH, et al: Preserving fertility after cancer. CA: A Cancer Journal for Clinicians 55:211-28; quiz 263-4, 2005.
The Oncofertility Consortium. Found at: http://oncofertility.northwestern.edu/for-patients
Thomson, AB, Critchley, H, Kelnar, CJ and WHB Wallace: Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation. Best Practice & Research Clinical Endocrinology & Metabolism, 16(2) 311-334, 2002.
Wallace, WH & TW Kelsey: Ovarian reserve and reproductive age may be determined from measurement of ovarian volume by transvaginal sonography. Human Reproduction 19:1612-1617, 2004