Parenthood after Cancer: Fertility Options from Diagnosis to Survivorship
About the Lecture
A cancer diagnosis means many stressful and life changing decisions. Although discussions about the desire to have a biological child in the future may not be seem to be a high priority. This is important for both men and women because cancer treatment may cause subfertility with difficulty conceiving a child or infertility without the ability to conceive a child with one’s own genetic material. Dr. Kuo will discuss recent advances in fertility preservation techniques available now to increase the probability of having biological children in the future. For cancer survivors, fertility treatment options also exist to maximize parenthood. The goal of this lecture is to help patients, their family members and others interested in future parenthood to be as well educated as possible in the treatment options available today.
John Kuo, MD, PhD is an Assistant Professor in the Department of Obstetrics and Gynecology at the David Geffen School of Medicine at UCLA. He serves as the Oncofertility Program Director for the Division of Reproductive Endocrinology and Infertility at UCLA. He has participated in the development and coordination of comprehensive fertility preservation and treatment services for both cancer patients and survivors. His clinical practice involves cancer patient counseling and education on current medical and surgical techniques available to preserve fertility and maximize parenthood after cancer treatment.
Alice Crisci is a young-adult breast cancer survivor and founder of Fertile Action, a non-profit helping women touched by cancer become mothers. She sits on a number of non-profit and university committees with Oncofertility Programs. She testified for the first Fertility Preservation bill in the nation and was instrumental in catalyzing a national bill that would cover fertility preservation for service members. She contributes regular opinion articles to HyperVocal.com, Fertility Authority, The University of Colorado and the Oncofertility Consortium. She also published a book about her experience being diagnosed with breast cancer at an early-age called Too Young for This. She also launched the first egg-donor and surrogacy grant program in the country through Fertile Action and the only pro-bono egg freezing network in the country.
This is a summary of a lecture presented on April 9, 2013.
Getting a cancer diagnosis can be devastating for many reasons, but if you are young and in your fertile or pre-fertile years that diagnosis becomes even more challenging. For most patients the overwhelming anxiety of the diagnosis is just beginning to be absorbed, and you and your doctors are beginning to make decisions to treat a life-threatening diagnosis. A patient in his or her fertile or pre-fertile years may not even be thinking about or ready to start thinking about having a family. It adds a layer of complication to your cancer treatment if fertility preservation is to be considered, and there is no luxury of time. Fertility planning and preservation can be very complex for women and has expenses associated with it that may present additional burdens for young people. A complicating array of decisions becomes more complicated.
Alice Crisci remembers the story of her own diagnosis of cancer and how within hours she had to begin making decisions. She always had envisioned parenthood; to her the fear of losing the possibility of being a mother seemed greater than even the fear of dying. She remembers her feelings of hopelessness and despair, the realization of her partner did not intend to be in the relationship long enough to consider children and the devastation that at the time she was diagnosed that she would have to freeze fertilized eggs because embryos survived better than unfertilized eggs. Faced with a sperm donor catalogue and five days to choose the potential genetic father of her potential children was overwhelming and laden with emotion. All she could think was “I’m too young for this,” and this became the title of the book that represented her outpouring of emotions during this time. Her life changed dramatically and her experience became the catalyst for her vision and investment to help other cancer patients get the information they need about fertility preservation and to help fund these services for young adults touched by cancer through her organization, Fertile Action.
Cancer is toxic to fertility. Approximately 11% of all cancer diagnoses are made in individuals in their reproductive years. The damage to the gonads (ovaries and testes) from chemotherapy and radiation is both age and gender related. Pre-pubertal ovaries are less vulnerable to chemotherapy and radiation than adult ovaries, so for females the earlier chemotherapy occurs, the greater the likelihood the ovaries will recover. At the time of puberty, women have approximately 300,000-500,000 oocytes (eggs) in their ovaries. By menopause that number drops into the 100’s. The more eggs present at the time of the chemotherapy, the greater the number that will survive. However, the opposite is true for men. Pre-pubertal testes are more vulnerable to chemotherapy and radiation than adult testes.
Radiation has complications for fertility, and it is also different for males and females. Researchers have identified the specific levels of radiation exposure toxic to the eggs (oocytes) for females and the cells that create sperm for males. The levels are referred to as Gray’s and are abbreviated Gy after the person who discovered this standardized measure of absorption of radiation. For example, the median lethal dose for oocytes is 1.99 Gy for females. Sterilizing dosages occur as 20.3 Gy at birth, 18.4 Gy at 10 years of age, 16.5 Gy at 20 years and 14.3 Gy at 30 years. High dose ranges of 14-30 Gy radiation to the uterus can also cause uterine dysfunction. A pre-pubertal uterus is more vulnerable to radiation. It is likely to cause a smaller uterus with increased obstetrical complications. For males, there can be structural and quantitative changes in the spermatogonia (the cells in the male testes that develop and divide to form spermatocytes) with 0.1 Gy of radiation. A threshold of 1.4 Gy can lead to having no measureable level of sperm in the semen. Leydig cells, which produce testosterone, are more resistant than spermatogonia and function with up to 20 Gy in the pre-pubertal period or 30 Gy post puberty.
Chemotherapy also has its toxicities. “Alkylating agents” are drugs that work by binding to and interfering with normal DNA processing within the cancer cell to prevent the cell from making the proteins it needs to grow and survive. This class of drugs is the most toxic for ovaries and testes; examples are cyclophosphamide and cisplatin. The good news is that after chemotherapy we have no reports of uterine damage, which could impair carrying a pregnancy.
Approaching the issues of cancer and parenthood are sensitive as there can be late-onset consequences of cancer treatment; however, it is very important to discuss these issues prior to the onset of cancer treatment so that each patient has the knowledge to make decisions if they want to pursue whatever fertility preservation options might be available to them. Fertility is a topic that should always be addressed in pre-puberty and fertile individuals.
Female Fertility Preservation
There are a number of strategies to consider in a pre-pubertal female. Where appropriate, a lead apron should always be used during radiation to shield or protect the ovaries. However, shielding may not be possible if radiation is needed to the pelvic region. In addition, there can still be some scatter radiation that may have an impact; however, the consequences will be less severe. In situations where the shielding is impossible it may be possible to move the ovaries up and out of the radiation field through a surgical procedure. The risk of injury to the vascular supply of the ovaries and the fallopian tubes is also a potential complication. Ovarian tissue also can be preserved through cryopreservation for future transplantation back into the woman. Finally, there is some research on cryopreservation of in vitro maturation oocytes obtained from ovarian follicle aspiration or ovarian tissue dissection.
For post-pubertal women, ovarian shielding should also be done during radiation where applicable. Moving the ovaries out of the field is also possible to avoid radiation exposure. Similar to pre-pubertal women, cryopreservation of ovarian tissue for future transplantation also can be done. Cryopreservation of the eggs after a process of harvesting the eggs and in vitro maturation is also possible. In vitro fertilization (IVF) is an additional option. This involves using hormones to stimulate the maturation and release of eggs, which are then harvested. These mature oocytes (eggs) can then be frozen through cryopreservation and/or they can be fertilized in the lab (in vitro) and then frozen as embryos. Finally, there is a controversial process, which has been done where the patient is given a gonadotropin releasing hormone (GnRH agonist/antagonist) to suppress the ovary so that it is metabolically inactive. By doing this, the ovary will receive less exposure to harmful chemicals and may be less likely to be damaged.
The first IVF baby was born in 1978. Since that time, much has been learned about this process and how best to manage it. Depending on where a woman is in her cycle, the process of IVF can take 2-6 weeks, which may delay treatment that amount of time. IVF involves first suppressing the ovaries, then stimulating them to mature eggs while at the same time preventing the ovaries from releasing the eggs. A trigger injection is given that releases the eggs, which are retrieved. Ultrasound is used to view the ovary; the physician inserts the needle through the wall of the vagina into the ovary and removes the eggs. The fluid and the eggs are aspirated into a tube, which is then separated at the lab. For some women, they will freeze their eggs, a process that has only recently become a good viable option. Others will choose to have their eggs fertilized and allowed to mature several days and then they are frozen as embryos.
The first human live birth after oocyte (egg) cryopreservation was reported in 1986. The number of live births per oocyte retrieved is very low (3%-5%). In October 2012 the American Society of Reproductive Medicine released a statement that oocyte cryopreservation is no longer considered experimental in patients with cancer. A study that reviewed 936 live births found no increase in congenital malformations, suggesting that this is a safe and viable means of preserving fertility. This option is particularly appealing for women who may not have a partner at the time of the cancer diagnosis/fertility preservation, thus allowing the possibility of having a genetic child who is both hers and her future partner’s.
One concern with IVF is whether the hormone stimulation used for maturing eggs and stimulating their release might be harmful for women with estrogen sensitive cancers, such as some of the breast cancers. In one study with estrogen sensitive cancer, IVF ovarian stimulation was done while also using letrozole to inhibit estrogen synthesis. In this study they did not find an increase in cancer recurrence.
Not all women have the luxury of the 2-6 week process needed for IVF; thus, a quicker approach was developed called “random-start IVF stimulation.” In this situation, the woman does not have to wait for her period, but rather, at any point in the cycle, begins the GnRH Antagonist along with the gonadotropins. After two weeks there is a trigger injection for release and egg retrieval. The advantage of this is that it might only delay chemotherapy treatments by two weeks. The disadvantages are that there are likely to be fewer oocytes obtained and fewer embryos for fertilization. It is unknown if the quality of the eggs decreases when stimulated in a high estrogen and progesterone environment. As of now there have been no human live births reported yet from this somewhat controversial procedure.
One experimental procedure aims to retrieve immature oocytes at any time from unstimulated ovaries during the menstrual cycle and then mature them in vitro. Once the oocytes are mature, they can be fertilized and cryopreserved or the mature oocytes can be cryopreserved. The first successful human in vitro maturation was reported in 1991. The advantages of this is that ovarian stimulation is not needed, there is a lower cost without gonadotropin use and minimal delay before cancer treatment. The disadvantages are that there have been a high rate of genetic abnormalities, suboptimal embryo development and implantation and lower success rates than standard IVF. In mice, live offspring have been demonstrated but not in humans as of yet.
Another experimental approach is “autotranplantation.” In this process the ovary/ovarian tissue is harvested before chemotherapy. It is then sliced into small strips and these strips are cryopreserved. They can later be transplanted back inside the pelvis. About 15 women, approximately a third of those who underwent transplant, have given birth. Currently no human case of whole ovary transplantation after cryopreservation has been successful. The tissues need to be thin for cryopreservation. Autotranplantation is problematic. There is often major follicle loss of 50-90% from that ovary. There is limited ovarian function (up to three years), and there is difficulty cryopreserving the whole ovary. There is also concern about the potential seeding of malignant cells (e.g., leukemias, neuroblastoma, and breast cancer) back into the patient when the tissue is returned. Overall, there has been limited experience with this procedure which is still considered experimental.
Male Fertility Preservation
For males, sperm production occurs on average at age 13.4 years with a range of 11.7 to 15.3 years. Any damage along the genital tract will affect fertility. Pre-pubertal preservation includes shielding the genital tract from radiation. Sperm aspiration or extraction can be done for possible immature spermatocytes or spermatids. Researchers are also experimenting with testicular tissue cryopreservation for future transplantation; however, this has the potential for reintroducing malignant cells.
Post-puberty preservation also includes shielding the genital area from radiation. Testicular sperm extraction or epididymal aspiration is also possible. This is a process by which the sperm may not be present in semen or have other damage making them unable to be used for intrauterine fertilization. Testicular tissue cryopreservation for future transplantation is also possible.
The best possibility of preserving fertility in post pubescent males is to bank as much sperm as possible. Sperm cryopreservation by masturbation, vibratory stimulation or electro ejaculation can all lead to fertility preservation. The advantage of this is that there is no delay in treatment with this procedure.
For men who have a limited amount of sperm banked, there is also a procedure called intracytoplasmic sperm injection (ICSI), a method by which sperm is injected into the egg. It requires fewer sperm and the sperm not used can be refrozen. The first human babies from ICSI were reported in 1992. Successful births have occurred with immature round spermatids, secondary spermatocytes, and in vitro matured primary spermatocytes to mature spermatids which resulted in a twin live birth.
Testicular suppression with GnRh analogs or antagonist has been uniformly ineffective in either preserving fertility in males or speeding recovery of spermatogenesis (the development of sperm from germ cells).
Fertility Testing and Fertility Options
For women, levels of anti-Müllerian hormone (AMH) and FSH and estradiol levels on day three of a woman’s menstrual cycle are important in evaluating potential fertility. By using ultrasound, a baseline follicle count can be done to assess the ovarian reserve. For men, semen analysis that includes the volume of the ejaculate and how well they swim are important. Sperm concentrations are correlated positively with testicular volume and inhibin B, but negatively with FSH.
Age is a significant factor for fertility in all women. For women without prior cancer history, fertility decreases rapidly after the age of 29 and miscarriage rates begin to rise after age 35. Women who have undergone cancer treatment often wonder if they will regain their menstrual cycles because their treatment temporarily can stop menstruation. The younger the woman is at the time of her treatment, the greater the likelihood that her cycle will resume. The older the woman is, the greater the likelihood that she may be pushed into permanent menopause.
Clomiphen citrate (Clomid) is used for all women, whether they have had cancer or not. It is most common for women with ovulatory dysfunction, younger women, those with short luteal phase or women who are unable or unwilling to pursue more aggressive treatments. The pregnancy rate is 15%. The negatives include impaired endometrial growth (which could lead to reduced pregnancy rate), and it can also decrease the quantity and quality of cervical mucus. One of the risks of using Clomid is multiple births, mostly twins.
Another option is gonadotropin injections, which can increase pregnancy rates by 5-25% per cycle. They often produce multifollicular growth with favorable endometrial lining and cervical mucus. The negatives include a variable response between women and even in different cycles in the same woman. This option can be costly and requires daily injections, frequent ultrasounds and blood monitoring, and higher estradiol levels with side effects from ovarian enlargement. The risks include cycle cancellation, multiple births, and ovarian hyperstimulation syndrome.
Intrauterine insemination also can be done by taking the sperm, spinning them down and placing a higher number of sperm near the released egg to increase the likelihood of fertilization.
As discussed earlier, in vitro fertilization is also a treatment for infertility. If there is a problem because of the aging of eggs or too few eggs, a donor egg can be used from a younger woman. Aging does not have as significant an adverse effect on the uterus as it does with eggs.
There are additional options that include having a gestational surrogate, which is someone who carries the pregnancy. That egg could be from a different donor or from the surrogate. In addition, adoption is another means of becoming a parent that should be considered and explored as well.
The UCLA Fertility and Reproductive Health Center can be contacted at 310 794-7274.
Fertile Action is a cancer charity that help women touched by cancer become mothers through education, advocacy and financial aid for fertility preservation, sperm donation, egg donation, surrogacy and long-term storage of sperm, oocytes, and embryos. Fertile Action educates, advocates, supports and provides financial aid. Its goal is to provide empowering education to patients and physicians, to decrease fertility preservation costs by more than 50% through their network and offer fertility scholarships on a sliding scale basis. They advocate that oncologists have conversations about fertility with patients during the treatment planning phase. Fertile Action was founded by Alice Crisci after her own personal experience to preserve her fertility during her breast cancer treatment. They can be found at www.fertileaction.org on the web.
In sum, cancer has many implications for individuals who have not yet had the opportunity to become parents. Becoming a parent comes in many different forms and there are broader choices available now than ever before. More importantly, in pre-fertile and fertile individuals, cancer treatment should include an immediate consultation with someone well versed in options for fertility preservation alongside their recommendations for cancer treatment. While most individuals want to begin their cancer treatments as soon as possible, and time is not a luxury during this process, each patient should have their questions explored and addressed. Once cancer is treated, patients need to address their options for parenthood. Exploration is not just the medical aspects of fertility but also the psychological consequences. These consequences may be felt immediately or may be delayed but whenever they surface they are real and deserve a multidisciplinary approach and consideration.