Both chemotherapy and radiation therapy are toxic to the gonads: ovaries in females and testes in males. Females are born with a limited number of eggs, which are stored in the ovaries. In females, damage to the ovaries depletes this egg supply and results in premature ovarian insufficiency (also sometimes called premature ovarian failure or premature menopause). This often causes infertility and symptoms related to low estrogen levels, such as hot flashes, night sweats and mood changes. In males, damage to the testes is likely to result in lower sperm production, but hormone production is less likely to be impaired. Therefore, sexual function may continue normally in spite of decreased or absent sperm production.

The effects of treatment depend on the chemotherapy medication used, the total dose and the patient’s age at the time of treatment. Radiation in general is more damaging to the ovaries and testes than chemotherapy, and the specific risk is associated with the location in which the radiation therapy will be targeted.

In general, the gonads of boys and girls are less sensitive to the effects of chemotherapy before the onset of puberty. Both boys and girls may go through a normal puberty and have normal reproductive function for a while, in spite of treatment during childhood or early adolescence. In girls, there is a risk of early menopause in the 20s or 30s. However, certain high-dose chemotherapy regimens in young children may result in failure for puberty to start at all. Radiation therapy to the pelvis or abdomen in boys or girls may cause enough damage to the gonads that puberty does not occur normally.

In girls, the ovaries are very sensitive to chemotherapy and radiation after puberty, and even more so as they get older. Women are born with all the eggs they will ever have. Women who are younger than 25 years old may have some eggs remaining after chemotherapy because their ovaries contain more eggs than older women. Even if their reproductive function seems to be intact after treatment (periods continue normally), they often have a risk of early menopause. For women who are older, the risk of depleting the egg supply after cancer treatment is higher because they are starting treatment with a lower number of eggs than their younger counterparts.

After puberty, sperm production is very sensitive to chemotherapy and radiation. Radiation to the pelvis or directly to the testicles will stop sperm production. Radiation to the upper leg or upper abdomen may cause some damage to the testicles, but sperm production may recover in these cases. Radiation therapy related to bone marrow transplantation is associated with a very high risk of infertility in the future.

Some types of chemotherapy are known to be particularly toxic to the gonads. Alkylating agents, such as Cytoxan (cyclophosphamide), are particularly damaging to both ovaries and testicles. Even low-dose Cytoxan given over a long period of time (e.g., for treatment of systemic lupus, rheumatoid arthritis or kidney disorders) can have a detrimental effect. Others, such as methotrexate, have a much lower risk of damaging future fertility. Current cancer treatment protocols often contain many medications given in overlapping or alternating regimens. Very little is known about the long-term effects of these newer regimens, but they are likely to cause damage to the gonads.

Generally, yes. Women with cancers that are often responsive to hormones, particularly breast and uterine cancer, may be an exception to this rule. Although some breast cancers are believed to be stimulated by estrogen, and there are high levels of estrogen in pregnancy, there is currently no evidence that pregnancy after breast cancer increases the risk of recurrence or spread. This is a controversial area, and women with breast cancer should consider their options very carefully after a discussion with their oncologist. Before considering pregnancy, it is advised women wait a certain number of years after cancer treatment to reduce the risk of recurrence during pregnancy. Women with early uterine cancers may still be candidates for pregnancy if the cancer can be treated conservatively without a hysterectomy. 

Women who have had radiation to the pelvis or lower abdomen require special consideration with regard to pregnancy. If the uterus has been exposed to high doses of radiation, the endometrium (or inner lining of the uterus) may be destroyed. In this case, periods will have stopped, and it will not be possible for the uterus to support a pregnancy. In addition, women who have had radiation to the uterus have a higher risk of miscarriage, early delivery, fetal growth restriction and other complications because the blood supply to the uterus is compromised and may not be able to increase as much as is necessary to support a pregnancy.

Women who have received high doses of adriamycin and/or radiation to the chest may also experience complications during pregnancy as these treatments could compromise cardiac function. In pregnancy, the heart has to work considerably harder to pump an increased volume of blood to the baby. If the heart muscle has been damaged, it may not be apparent until an increased stress (such as pregnancy) is placed on the heart, and then heart failure can develop. Women who have had adriamycin treatment and/or radiation to the chest require careful evaluation by a cardiologist and careful follow-up in pregnancy to avoid serious complications.

Treatment of cancer during pregnancy can pose a serious risk to the developing fetus. But for men and women who have completed their cancer treatment some time before pregnancy, there does not seem to be an increased risk of birth defects, miscarriages or stillbirths as a result of their treatment. Some cancers are known to run in families, and it is likely that the offspring of these cancer patients could be at increased risk of developing the cancer also. You should discuss your particular risk factor with your oncologist or with a genetic counselor. Other than those cancers known to run in families, the risk of cancer in the offspring of cancer patients does not seem to be increased.

Surgical

Treatment for early cervical cancer or endometrial cancer generally includes hysterectomy. In a few select cases, this may not be necessary. In very early endometrial cancer, it is sometimes possible to treat the cancer hormonally without removing the uterus.

In very early cervical cancer, for example, removal of just the cervix (called trachelectomy) may be possible in order to retain childbearing potential. If you are a candidate for this type of fertility-sparing surgery, your gynecologic oncologist can tell you more about the benefits and limitations of such procedures.

If radiation to the pelvis is required, the ovaries can sometimes be moved out of the area expected to receive the most radiation. This procedure (called ovarian transposition, or oophoropexy) can at least partially protect the ovaries from the effects of radiation.

While ovarian cancer is frequently treated by hysterectomy and removal of both ovaries, early stages can sometimes be safely treated by removal of the affected ovary only. For certain ovarian masses, patients may be candidates for fertility-sparing ovarian cystectomy.

These possibilities should be discussed with a gynecologic oncologist.

Embryo Cryopreservation

In vitro fertilization (IVF) followed by cryopreservation (freezing) of the resulting embryos can provide an opportunity to have a pregnancy after cancer treatment is completed. This procedure involves treatment with injectable fertility medications to stimulate development of multiple eggs. The eggs are retrieved in a procedure performed under anesthesia, called an oocyte retrieval, and fertilized with the partner’s (or donor) sperm. The resulting embryos are frozen after growing in the lab for several days. Sometimes it is not possible to proceed with an IVF cycle because of the need to start cancer treatment quickly. An IVF cycle takes about two weeks to complete; often, controlled ovarian hyperstimulation to harvest eggs can be started on a random day during a woman’s cycle.

IVF with cryopreservation of embryos has been used extensively for infertility treatment since the early 1980s, and it is considered a safe and routine procedure. The embryos can be stored for a number of years until cancer treatment is completed. Even if the cancer treatment results in ovarian failure, the woman can be given hormones to prepare the uterus to carry a pregnancy, and then the embryos are transferred back to the uterus by a simple outpatient procedure. The chance of pregnancy is about 30% to 50% each time one to two embryos are returned to the hormonally prepared uterus (pregnancy rate is dependent on maternal age at the time the embryos were created). If several high-grade embryos can be produced and stored, that should give the couple a reasonably good chance of achieving a pregnancy at a later date.

Cryopreservation of Unfertilized Eggs (Oocyte Cryopreservation)

Women who do not have a partner can still go through an IVF cycle and freeze their unfertilized eggs. Freezing eggs is a newer technology than embryo cryopreservation, and was considered experimental until 2012. Eggs have been more difficult to freeze then embryos because the egg is the largest cell in the human body and has a large amount of water, which can cause ice crystals to form and damage the egg. A new type of freezing called vitrification, which is flash freezing of the eggs while preventing ice crystals from forming, has made egg freezing much more efficient. In the future, cryopreserved eggs can be thawed and inseminated with sperm to create embryos for a pregnancy attempt.

Cryopreservation of Ovarian Tissue

Ovarian tissue cryopreservation is an emerging option for fertility preservation. It involves harvesting ovarian tissue and freezing it for future use. Harvesting this tissue requires a surgical procedure, usually a laparoscopy. One benefit of this option is it can be done immediately, and therefore will not delay cancer treatment. It is also the only fertility preservation option available to prepubertal girls. A piece of ovary cortex (the tissue on the outside of the ovary) in a young woman contains thousands of eggs. Once cryopreserved, the ovarian tissue pieces can later be transplanted back into the patient for future pregnancy. Because this is a new technique, it was considered experimental until very recently (2019). To date, at least 130 babies have been born after transplantation of cryopreserved ovarian tissue.

Medical Suppression of the Ovaries

It is thought that making the ovaries less metabolically active can protect them from the damaging effects of chemotherapy. This can be done by temporarily “turning off” or suppressing the ovaries with a special medication. The medication most commonly used in the United States for ovarian suppression is leuprolide acetate (Lupron Depot), which is given by injection either monthly or every three months. Preferably, it should be given at least seven to 10 days before the start of chemotherapy. This medication also has the effect of stopping menstrual periods. This can be useful because chemotherapy often lowers the platelet count, increasing the risk of heavy or prolonged bleeding during menstrual periods. Other side effects of Lupron include hot flashes and vaginal dryness. If these symptoms become troublesome, hormone therapy can be used to help with those symptoms.

It is important to assess residual ovarian function after treatment for cancer. If menstrual periods have stopped, and especially if menopausal symptoms are present (e.g., hot flashes and night sweats), the ovaries have likely been damaged. Generally, a blood test for follicle stimulating hormone (FSH) and estrogen will indicate whether the ovaries are still functioning. The anti-Mullerian hormone (AMH) blood test can also help measure the long-term egg supply. If the blood tests indicate the ovaries are not functioning, the ovaries may or may not recover. Sometimes periods start up again several months after the completion of treatment. Frequently after cancer treatment, women have very low egg supplies and may have periods of intermittent ovarian function. For women who would like to be pregnant after cancer treatment, it’s important that they see a fertility specialist as early as possible for evaluation and to discuss options.

For women in whom there seems to be no residual ovarian function, it is possible to get pregnant and carry a pregnancy using donor eggs (oocytes). In some cases, the donor is known to the recipient (such as a sister or friend), but more commonly, women use anonymous donors. The donor is treated with fertility drugs so that she will produce a large number of eggs. After egg retrieval, the eggs are fertilized with sperm from the recipient’s partner or from a donor. The fertilized eggs are placed into the uterus of the recipient after priming with hormones so that the uterus is prepared to accept the pregnancy. Most fertility centers have a donor oocyte program and accept patients up to the age of 50–55. The success rate using anonymous donors is about 50% per attempt.

Sperm Cryopreservation

The best way for men to preserve their reproductive potential at this point is to cryopreserve (freeze) and store sperm. In the past, this was not always a good option because many men with cancer have sperm counts that are less than normal. However, now with in-vitro fertilization and ICSI (intracytoplasmic sperm injection), even very small numbers of sperm can be used to establish a pregnancy.

In order to cryopreserve sperm, the man must be able to produce a semen sample, generally by masturbation. Fairly young men/teenagers should be able to produce a specimen suitable for cryopreservation, but in younger men, the subject can be difficult to bring up or discuss. The semen needs to be delivered promptly to a lab capable of freezing it properly. Ideally the semen sample would be collected right there in the lab. Most labs have a small private room available for this purpose.

If possible and if time permits, several semen specimens should be cryopreserved at intervals of two to three days. Most men can delay treatment for several days or a week for this purpose.

Shielding the Testicles from Radiation

If radiation to the pelvis is part of the treatment plan, a patient and his physician may want to discuss the possibility of shielding the testicles from radiation in selected cases with testicular cancer on one side. However, shielding the testes is not recommended for many patients due to the risk of immune cells or cancer cells that may have spread to the testicular tissue. Cure of the cancer is, of course, the most important consideration, so sometimes it will not be possible to shield the testicles and adequately treat the cancer.

In some experimental settings, pieces of testicular tissue from young boys have been cryopreserved in the hope that the tissue might produce sperm in a laboratory culture one day or that the tissue can somehow be returned to the testicle and function.