In a woman of reproductive age, one of the two ovaries begins to develop 15-20 immature eggs (oocytes) within follicles (cells which support its development) every month. Only one of these oocytes is permitted to fully develop and become a mature oocyte (the rest die), at which point it is released into the fallopian tube for possible fertilization in the uterus. A woman has a limited number of oocytes in her lifetime, with the highest number being present prior to birth (about 7 million at 7 months gestation). This number then slowly decreases from approximately 2 million at birth, to menopause, when approximately only 1,000 oocytes remain and stop maturing. Over a lifetime, approximately 400-500 mature oocytes are released into the fallopian tubes. If the immature oocytes stored within the ovary are damaged by cancer treatment, fertility is at risk. Damage can be to the undeveloped oocytes or to the follicles required to develop them. In addition, a woman needs to be able to carry a pregnancy to term. Damage to the uterus or cervix can compromise this ability.
It is important to understand that chemotherapy works by killing rapidly dividing cells. Chemotherapy is able to destroy large numbers of cancer cells because they are rapidly dividing and abnormally reproducing. Many other cells in our bodies are also constantly dividing, including those lining the gastrointestinal tract, hair follicles, and germ cells (including sperm and oocytes or eggs). Because these cells also become targets, we see side effects related to their destruction, such as diarrhea, mouth sores, hair loss, and infertility, respectively.
One other piece to the puzzle is the pituitary gland, located in the brain. This gland produces special hormones (LH and FSH), which in turn stimulate the ovary to develop and release a mature female oocyte. Radiation therapy to the brain can damage the pituitary gland, ultimately affecting the ovulation cycle, which may then result in a shorter luteal phase (days after ovulation during which fertilization occurs). This can usually be fixed with supplemental hormones.
Predicting the risk of infertility to each individual is often impossible. Risk is dependent on the drug(s) used, dosage received, duration of use, and the woman's age at the time of administration. Rarely does a person receive only one chemotherapy agent, and combining various agents makes predicting fertility a greater challenge. Higher doses and longer duration of treatment cause the highest risk of infertility. Older age at time of administration leads to a higher likelihood of infertility and amenorrhea (loss of menstruation). As age increases, smaller doses of chemotherapy are needed to result in infertility.
Fertility loss is also dependent on the size of the follicle pool (or number of oocytes) prior to chemotherapy. Given that this number decreases with age, the older the woman, the higher the risk of infertility becomes, because there are fewer oocytes at the outset. Unfortunately, there is no way to know for certain how many oocytes a woman has at any point in life, although 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) For example, a study of amenorrhea in breast cancer survivors who received cyclophosphamide, methotrexate, and fluorouracil (CMF) found that 35-40% of women under age 40 did not regain menses, but as many as 80-95% of those over 40 did not. This means that somewhere between 5 and 20% of women over 40 DID regain menstruation, even though they were not expected to do so.
Many studies look at the resumption of the menstrual cycle as a predictor of fertility. Although pregnancy can not occur without resumption of menses, menstruation alone is not a guarantee of fertility. Some studies have reported pregnancy rates in survivors, but it is difficult to know how many were actually attempting to conceive. One must also consider other variables, including rates of intercourse, partner fertility issues, cancer therapies received, and time since therapy. Women who do regain menses after therapy are still at risk of entering 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, and busulfan. Some agents known to have a low risk of infertility are vincristine, methotrexate, and fluorouracil (5-FU). There is not enough data on newer agents, including taxanes and targeted therapies, to address fertility after these agents. Therapies used in preparation for stem cell and bone marrow transplant are likely to cause infertility in women, although studies have found that pre-pubescent girls treated for childhood cancers have a good chance of regaining ovarian function. Transplant regimens utilizing busulfan and/or cyclophosphamide are more toxic to a woman's fertility than those utilizing melphalan.
Damage to fertility caused by radiation therapy is dependent on the dosage received, area 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 related 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 abdomen as children, 97% experienced ovarian failure or developed menopause earlier than normal (average age at menopause was 23 years in these survivors). As a reference, 50 Gy is typically recommended for the treatment of common gynecologic cancers.
Younger women who do regain menses after radiation therapy are not out of the woods. These women are at risk of entering menopause earlier than women who did not have radiation or chemotherapy. Predicting when this menopause will occur is difficult, putting pressure on younger women who wish to pursue a natural pregnancy. As with chemotherapy, women who resume menses have no guarantee of fertility.
Total body irradiation (TBI) is a technique used for preparation for stem cell and bone marrow transplants in which the entire body is irradiated. It is estimated that 85-90% of women who undergo TBI will have permanent ovarian failure, with only 10-14% regaining menses. Pregnancy rates in women who received TBI for transplant are reportedly around 2% (although as high as 12% in aplastic anemia survivors). Girls who have received TBI prior to puberty are more likely to regain ovarian function than those who received it post-puberty.
Radiation therapy to the abdomen or pelvis can cause damage to the uterus and/or cervix, leading to difficulty carrying a pregnancy to term. Studies have found that radiation can cause changes to the musculature, blood flow, and size of the uterus. This may prevent an embryo from implanting. Other complications that occur in higher rates in women who received radiation to the uterus include: miscarriage (38% vs. 12% in the general population), preterm labor (62% vs. 9%), and low birth weight babies (62% vs. 6%). Despite these risks, the risk of malformations of the fetus are not increased, so long as radiation is not given during pregnancy.
Surgery that removes both ovaries or the uterus, cervix, and/or fallopian tubes will affect fertility in some way. Depending on the involvement and stage of the cancer, some women may be eligible for fertility-preserving surgeries and should discuss these options 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 drug should be stopped immediately due to the risk for the fetus. In addition, tamoxifen can alter estradiol and FSH levels, making it difficult to assess ovarian function in women on the drug (see assessment of ovarian function below).
Many studies conducted in the oncology community use the resumption of menses as a measure of ovarian function. Fertility experts know this is not a good predictor of fertility, and although there is no foolproof predictor, there are a few tests that can help unravel the mystery. Follicle stimulating hormone (FSH) and estradiol (E 2 ) are hormone levels which can be checked by a blood test on the 3 rd day of menstruation. These levels are used to assess ovarian follicle reserve and fertility. In a menstruating woman, an FSH above 12mIU indicates severely impaired fertility, as does an E 2 level above 75pg/ml.
These levels, however, cannot predict exactly how many follicles remain or how long before infertility will develop. One hormone, anti-Mullerian hormone (AMH), is produced 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 maturing) on the 3 rd 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 may be useful in predicting future fertility in women taking tamoxifen.
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 include families with genetic cancer syndromes).
The DNA of oocytes can be damaged 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. Individual women should discuss their own case with their oncology team and may benefit from consulting with a fertility specialist 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. Few studies have looked at this risk, but those that have studied this found that pregnancy does not appear to increase the risk of recurrence. These studies did not take under consideration if the tumors were ER or PR positive, an issue which requires more investigation. Studies have not examined if it is safe for breast cancer survivors to take fertility medications if they are unable to conceive naturally.
There are fewer well established options for fertility preservation in women compared to in men. The majority of techniques require 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 available options and some still in development.
Cryopreservation (freezing) of eggs or embryos requires the same collection process, which can take 2-4 weeks. Fertility-stimulating drugs are given in order to allow the release and collection of several mature oocytes. There is concern about women with potentially hormone-sensitive tumors receiving these drugs. Studies are looking at giving an estrogen-blocking drug, such as tamoxifen or letrozole, concurrently with the ovary stimulation to be safer in these women, and early studies look promising.
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 find this acceptable. This technique has a pregnancy rate of 20-25% once the embryo is thawed and implanted. There is considerable cost associated with this, ranging from $8-12,000, which does not include the cost of storage (approximately $350/year), thawing, and implanting.
Cryopreservation of eggs does not require sperm because these eggs are frozen unfertilized. Unfertilized eggs are more sensitive to the freezing process, and therefore pregnancy rates are much lower. There is approximately a 2% chance of pregnancy for each thawed egg. The costs are essentially the same as embryo cryopreservation.
This procedure can be used to decrease the ovaries' exposure if pelvic radiation is needed. Typically, one ovary is surgically moved to another area out of the radiation field. This is often done in conjunction with a therapeutic surgery for the cancer, but can be performed laparoscopically for women who do not require other surgery. This procedure has been performed for more than 40 years, with success rates reported anywhere between 16 and 90%. It is thought that damage to the blood vessels feeding the ovaries and “scatter” radiation (small amounts of radiation out of the main field) reaching the ovary may be to blame for lower success rates. 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 is uncertain, but if it is done during a cancer surgery, there may be very little cost associated with it.
Ovarian tissue freezing is still in the investigational stages, with only a few live births reported to date. One potential advantage for this technique is that it may be an option for young girls who have not reached puberty when receiving cancer therapy. Using a laparoscopic technique, multiple fragments of ovarian tissue are taken prior to the start of therapy. It is reported that 5 tissue fragments can yield 3500 follicles, which is necessary since up to 60% of follicles are lost to the freezing process.
There are several possible ways to utilize 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 utilized through in-vitro fertilization procedures. This is the only tissue-preserving method that has produced live human births to date.
Another technique being tested is xenotransplantation, where the ovarian tissue is implanted in another species (usually mice) and allowed to mature, leading to obvious ethical concerns. The last and most promising option is in vitro maturation, which matures the tissue in the laboratory, then utilizes the mature oocytes for fertilization and implantation into the woman. This technique has lead to live births in mice and cows, but not in humans yet.
Many fertility clinics offer ovarian tissue freezing, but woman should be aware of the investigational nature and lack of proven success of this technique.
Radical trachelectomy is a procedure used in the treatment of cervical cancer, as an alternative to the more standard surgical treatment of hysterectomy. It is estimated that almost 50% of women diagnosed with cervical cancer under the age of 40 are eligible for some type of fertility-sparing procedure. Trachelectomy removes the cervix but leaves the uterus intact, and is best applied to early stage cases (stages IA and IB). It can be performed vaginally or through the abdomen. There is an estimated 53% chance of pregnancy over 5 years for women who have had the procedure, and there have been over 100 live births to date. These women will require 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 require IVF because of difficulty getting pregnant due to the lack of a cervix. These pregnancies are considered high-risk, and will require C-sections 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 portion of the cervix, and is only appropriate in very early stage cases. For very early stage endometrial cancers, D&C may be sufficient, but these cases require careful examination and an experienced physician for successful outcomes. Several small studies used hormone therapy to treat early stage endometrial cancers. These studies closely followed the women for recurrence and performed hysterectomy if needed. They reported that some patients had no evidence of disease after treatment with hormone therapy and documented pregnancies in 20 patients. In cases of ovarian cancer limited to one ovary, it may be possible to maintain the healthy ovary and uterus. Studies have reported survival rates similar to those treated with more radical surgery. These options are clearly limited to only early stage disease, but can be a wonderful option in those women with early stage disease wanting to preserve fertility.
One other method that has been tested is known as gonadoprotection. This works on the theory that germ cells are damaged by chemotherapy because they are rapidly dividing and reproducing. By administering medication to stunt the reproduction of these cells, perhaps they would be protected from the damage of chemotherapy. Investigators have attempted to do this with gonadotropin-releasing hormone (GnRH) agonists and antagonists or birth control pills. Studies have had mixed results and were small, making it hard to apply the results. Larger randomized studies are looking at these techniques.
Fertility-preserving techniques for women come at a sometimes significant cost. The majority of patients will not have coverage for fertility-sparing procedures through their health insurance. Eleven states now require insurance companies to cover infertility diagnosis and treatment, but this still does not always cover all of the necessary tests and procedures. 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.
Sharing Hope is a program administered by Fertile Hope that offers discount rates for cancer patients at participating fertility clinics. Fertile Hope also has a section on financial options for fertility preservation. Women should understand that rates can vary greatly and it may be worth shopping around. This might be a job to give to a friend who offers to help, as it can be a time- consuming effort.
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 currently available to them, which is unfortunately not always done.
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