Amidst all the turmoil of cancer diagnosis and figuring out how to beat it, you and your health care providers commonly forget that the odds are that you will survive your disease for many years to come. Loss of fertility is one of the most disheartening consequences of cancer treatment. This is a guide to all the young women and men diagnosed with cancer on how to preserve their ability to conceive after cancer treatment. Unfortunately, in the real world, you do not get timely information to be able to make an informed decision. Surveys of young women and men indicate that they are very interested in future fertility. Surveys of providers, however, points that in less than half the cases fertility issues are discussed or women are referred for consultation. Interestingly, when women inquire about fertility they are more likely to receive information about future fertility or referral to a specialist.
Call to Action: the notion that ‘I / you got cancer and would be lucky to sort it out’ should not stop young people and their physicians from planning for long term survivorship issues. It is really possible to lead quite a normal life after cancer treatment with thoughtful preparation and consultation with pertinent health care providers
Preservation of Fertility in Women
Who needs it and how its done?
Fertility is a key aspect of the quality of life for cancer patients of childbearing age.
Preservation of fertility is defined as the application of medical, surgical and laboratory procedures to preserve the potential of genetic parenthood in adults and children at risk of sterility before the end of natural reproductive lifespan (Gosden 2009).
Decrease or loss of fertility can take place due to exposure to medication (chemotherapy), radiation or surgery (e.g removal of the ovaries). The American Cancer Society estimates that cancer affects one in each 3 women living in the United States. Modern cancer treatment commonly involve exposure to chemotherapy and sometimes pelvic radiation. Cancer and its treatment though is not the only situation that affect fertility. Fertility can also be diminished by bone marrow transplantation and treatment of kidney disease usually due to lupus (lupus nephritis).
If you are a women or a man living in the United States and recently diagnosed with cancer or another condition that threatens your future ability to mother or father children, this lens is written with you in mind. The odds are you will beat your disease and survive for many years to come. Considering fertility-sparing options before starting disease treatment may greatly enhance your ability to conceive a biological child after cure.
Health Problems that Jeopardize Fertility
Who needs to consider fertility preservation?
a. In 2009 about 700,000 women will be diagnosed with cancer, about 10% of them under the age of 45. Breast cancer is the most common cancer affecting women. Each year bout 15,000 women will be diagnosed with breast cancer before 45 year. Women can also be diagnosed with leukemias, lymphomas, cancer of the colon, uterus, ovary, skin or thyroid gland. Treatment of all these cancers is associated with long term effects during the survivorship period including decline in fertility. The effects of cancer treatment go beyond the harm caused by the method of treatment itself to the time spent in treatment and time needed for follow up. This delay means women will probably attempt pregnancy several years later than they intended.
b. Women undergoing bone marrow transplantation for treatment of cancer, anemias (e.g sickle cell disease) and other diseases. The use of chemotherapy and radiation prior to transplantation is usually associated with fertility loss in the vast majority of patients.
c. Some women develop breast or ovarian cancers due to abnormality in breast cancer gene (BRCA1 & 2). Reducing the risk of future cancer may require removal of both ovaries with loss of fertility.
d. Women diagnosed with connective tissue disease (Systemic lupus, rheumatoid arthritis…) or autoimmune disease may have severe disease affecting their organs (e.g kidney). Chemotherapy is sometimes used to suppress their immunity which may lead to fertility decline. Moreover, the antibodies generated by the disease process may directly affect ovarian function.
e. Individuals exposed to accelerated loss of eggs due to genetic disease (e.g mosaic Turner syndrome) can also benefit from preservation of fertility
f. Fertility extension. Women delaying pregnancy for career or social reasons (no male partner at this time) can consider freezing their eggs or embryos (using donor sperm). This option was not studied in large population studies.
Effects of Cancer Treatment on Ovarian Function
In general the younger the woman, the more oocytes she harbors in the ovary and the higher the likelihood that some oocytes will remain in the ovary after treatment.
a. Chemotherapy and the Ovary. The use of chemotherapy can lead to fast loss of oocytes (eggs). Oocytes carry the genetic material that women pass to their children after fertilization by a sperm. The effect of these agents is variable depending on the drug, dose, frequency of administration, and age of the woman at the time of treatment. Cyclophosphamide is the most harmful agent for future fertility. These medication appear to cause loss of eggs through damage of its DNA and inducing spontaneous demise of the egg. There is no proven method that can prevent this loss.
b. Pelvic Radiation and the Ovary. Exposure of the ovary to radiation can damage the eggs and the remaining tissue of the ovary. The amount of radiation that leads to complete loss of ovarian function is dependent on the age. A dose of 1500cGy will sterilize the majority of women at age 30. Smaller doses will sterilize older women.
c. Time factor. Cancer treatment usually requires several months. For some cancers (e.g breast cancer) medical treatment (tamoxifen) is required for 2 to 5 years after surgery and chemotherapy. For others oncologists recommend a period of observation for 1 to 2 years. This will delay a woman’s plan to start a family to a later age when fewer oocytes remain in the ovary. Actually the effect of cancer treatment on the ovary appears to be similar. Continuous loss of eggs from the ovary takes place in all women. Cancer treatment accelerates this loss so that the number of eggs in the ovary would correspond to older age.
d. Pelvic Radiation and the Uterus. Exposure of the uterus to radiation increases the risk of miscarriage, preterm labor and abnormal pregnancy outcome.
Evaluation of Ovarian Function after Cancer Treatment
Tests that reflects fertility potential (egg production) in women
Although many think that resumption of menstruation after cancer treatment indicates that the woman retains the ability to conceive, this is not true. Some women have regular menses with near exhaustion of the eggs in the ovaries. Thus, menstruation is not a reliable indicator of the ability to conceive.
The function of the ovary before after cancer treatment can be evaluated using hormone tests and ultrasound.
1. Cycle day 2 or 3 FSH (follicle stimulating hormone, normal is less than 12mIU/mL)
3. Antimullerian hormone (AMH). This is a new and promising marker and appear to be more accurate than the other markers.
4. Vaginal ultrasound to evaluate the number of small follicles visible in the ovary.
Although these markers are more accurate than menstrual history, normal markers after treatment does not mean that ovarian function is completely preserved after exposure to treatment.
Here is a study that I did in 2006. I compared the response to fertility medication in women cancer survivors that were exposed to chemotherapy to those that present for fertility preservation prior to cancer treatment. The number of eggs obtained from those exposed to chemotherapy was much less than those not exposed.
Methods Used to Preserve Fertility in Women
How it is done?
Methods used to preserve fertility in women are generally divided into three categories:
Modification of cancer treatment plan to reduce damage to the ovaries and uterus:
1. Preserving one ovary in women affected with early ovarian cancer.
2. Preservation of the body of the uterus with removal of the cervix in early cervical cancer.
3. Use of progesterone treatment instead of removal of the uterus in endometrial cancer.
Protection of the ovaries from the damage caused by cancer treatment:
1. Ovarian transposition is a surgical procedure to move the ovaries upwards, away from radiation field before pelvic radiation. Results are variable as some scattered radiation still reaches the ovaries.
2. Protection of the ovaries from the effect of chemotherapy. GnRH agonists are a group of medications that suppress the master gland in the brain, preventing the release of the hormones that stimulate development of follicles in the ovaries. Although suggested, there is no proof that they actually protect the ovaries and improve the chance of pregnancy after the use of chemotherapy.
Low Temperature Storage of Embryos, Oocytes or Ovarian Tissue:
1. Embryo freezing
2. Oocyte freezing
3. Ovarian tissue Freezing
Because they are applicable to all types of cancer, I will go through these in some detail.
The standard method for women with a partner
This is considered the standard method for preservation of fertility. Its suitable for women with a male partner or accepting he use of donor sperm and when cancer treatment does not need to be started immediately.
This method entails stimulation of the ovary with medications and frequent monitoring of response using ultrasound and blood work. This stimulation usually requires 12 to 14 days.
The eggs are then removed from the ovary by an outpatient procedure under sedation. Egg retrieval requires passing a needle through the vagina into the ovary. Eggs are then fertilized in the lab and the resulting embryos are frozen 2 to 6 days later and stored for later use. Cancer treatment can start immediately after egg retrieval.
After cure, women can request to use their embryos, that are placed back into the uterus after simple preparation of the lining of the uterus. The transfer of two embryos into the uterus yields a pregnancy rate of about 30%.
Women diagnosed with an estrogen sensitive tumors (e.g. breast cancer, uterine cancer) require special attention to mitigate estrogen rise during stimulation.
Slow freezing and Vitrification
Egg freezing is considered for women with no male partner and declining the use of donor sperm. It requires stimulation of the ovaries and egg harvest as described earlier.
The human egg is unique. Its the largest cell in the body with high water contents. The membrane surrounding the cell is not very permeable. Moreover, its the only cell in the body where chromosomes are spread on flimsy structure called the spindle, rather than being enclosed inside the nucleus of the cell.
The egg requires special expertise to freeze. One of two techniques are used; slow freezing or vitrification (rapid freezing). The newer vitrification method has the advantage of minimizing the formation of ice crystals inside the egg and yields better survival of the egg at thawing.
The American Society for Reproductive Medicine still considers egg freezing experimental.
In Vitro Maturation
Growing eggs in the lab
In this method a very short ovarian stimulation for 3 to 5 days is performed followed by retrieval of immature eggs. Eggs are then matured in the lab, fertilized and the resulting embryos are frozen for later use. The efficiency of this method is lower than retrieving fully mature oocytes. About 50% of follicles punctured yield an egg. Approximately 70% of the eggs reach maturity in the lab and about 70% of those fertilize. This method is suitable for women demonstrating high response to stimulation to fertility medication.
Ovarian Tissue Freezing
This is an experimental method for preservation of fertility. In this method one ovary is removed, processed and frozen. After cure, the ovary is transplanted back in the pelvis (orthotopic) or under the skin (heterotopic). Processing of the ovary means that the outer 2-3mm (this is the part that contains the eggs-the cortex) is shelled out and cut into thin strips. So far the ovary cannot be frozen as a whole organ because its too thick for cryoprotectants (the substance that protects the tissue from damage caused by freezing) to diffuse into it before freezing. Removal of the ovary is performed using laparoscopy (minimal access surgery) or at the time of surgery for other indication.
The inner part of the ovary (does not contain eggs) is sent for tissue examination to make sure it does not contain any malignant cells. Since ovarian harvest can be accomplished in 1 to 2 hours, this method is used when there is no time to complete ovarian stimulation (2 to 3 weeks) or when stimulation of the ovary is not possible as in girls before puberty. Because of the experimental nature of the procedure, its offered to women with very high risk for ovarian failure after treatment.
Co-ordination of Cancer Treatment & Fertility Preservation
Multiple studies in the US surveying patients or oncologists found that discussion and referral for preservation of fertility takes place in less than 50% of patients. Referral was more likely when patients inquire about fertility issues.
This underlines the importance of educating women about fertility issues and the diagnosis of cancer and other allied diseases. Empowering women to ask questions appears to one of the most important initial steps to receive appropriate information about and possibly pursue preservation of fertility.