Infertility Problems in Cancer Survivors – The Psychological Impact of Infertility
Infertility is a common problem for those who have had cancer and cancer therapy. In recent years, improvements in cancer treatments have been developed to both prolong life and reduce the risk of infertility. New treatment options are making fertility a possibility for many cancer survivors.1
The human reproductive system is complex and unique for both sexes. The reproductive system is affected by many cancer-related therapies, with the end result of difficulty conceiving. Cancer therapy effects on fertility depend on the patient’s age, type of cancer, and method of treatment. In order to understand the causes of infertility related to cancer and cancer therapies, we will review the reproductive system and processes of ovulation, sperm production, and fertilization.
The reproductive axis is made up of the pituitary gland, the gonads (ovaries or testes), and the reproductive tract (the vagina, uterus, and fallopian tubes in women and the epididymis, vas deferens, penile urethra, and glands in men). In men, the seminal vesicles and prostate are the major glands responsible for semen production.
Women A woman’s oocytes (eggs) are completely formed during fetal development and stored in a resting pool in her two ovaries. After birth, the oocytes do not regenerate but rather decline with age; their depletion results in ovarian failure (menopause). The oocytes continually leave the resting pool, enter the growth phase, and die. When a woman reaches puberty, a complex cyclic process begins—the menstrual cycle—which rescues one of the oocytes from death and causes ovulation, which culminates in either pregnancy or a period (menses). The ovulatory cycle continues until menopause, which occurs on average at fifty-one years of age. Ovulation is controlled by follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are produced by the pituitary gland. Once expelled from the ovary, the oocyte is captured by the fallopian tube and is ready to be fertilized. If it is fertilized, the resulting embryo moves into the uterus and attaches to the uterine lining to continue development. During the ovulatory cycle the ovaries also produce estrogen and progesterone, which prepare the lining of the uterus for the embryo, thereby facilitating implantation and maintenance of a pregnancy. If the oocyte is not fertilized, the lining of the uterus is shed, resulting in a period.
Men In contrast to the female reproductive system, in the male reproductive system sperm production is initiated at puberty and continues throughout life. The testes contain stem cells that continually replenish the sperm pool. The ability to produce sperm depends on adequate amounts of FSH, LH, and testosterone. The sperm are stored in the epididymis until ejaculation. During intercourse, the sperm are transported through ducts along with secretions from the glands and are ejaculated through the penile urethra. The process of ejaculation requires intact nerves in the pelvis. The testes also produce testosterone, which controls sex drive and the ability to achieve an erection.
Cancer Therapy and Reproduction
Cancer therapies can cause a spectrum of damage to the reproductive axis. The damage may be severe and result in sterility (ovarian or testicular failure) or partial injury resulting in early menopause and infertility (inability to conceive within twelve months). Symptoms of ovarian failure include absence of menses, hot flashes, and vaginal dryness. Testicular failure can lead to loss of sex drive and ejaculation or erection difficulties.
The treatments for cancer that can affect the reproductive system include the following:
• Surgery on the reproductive organs
• Radiotherapy to abdomen and pelvis
Surgery Operations for cancer that do not involve the reproductive axis do not affect a woman’s ability to achieve pregnancy. However, if the operation involves removing parts of the reproductive system, it may cause sterility or infertility. For example, treatment for gynecological cancer may involve the removal of the uterus (a hysterectomy), ovaries (a bilateral oophorectomy), or some portion of the reproductive tract such as the cervix, vulva, or vagina. Some operations may involve these organs but spare reproductive function. However, the scar tissue that develops after surgery may hinder conception. The surgery that is performed will depend on the type of cancer and whether it has spread to other organs.
For a man, surgery may involve removing both testicles (a bilateral orchidectomy), which results in sterility. Operations that spare one or both testicles preserve the capacity to conceive; however, other surgeries that involve removing the prostate, bladder, or bowel or that cause damage to the nerves in the pelvic area can result in infertility or erectile dysfunction. Surgery in the pelvic area involving the lymph nodes may result in ejaculation difficulties.
Chemotherapy Chemotherapy targets tissues with actively dividing cells, such as skin, hair, the digestive tract, and the reproductive organs. The sperm and supporting cells of the oocyte divide during development. Therefore, all chemotherapies are potentially damaging to the ovaries and testes and may reduce the number of oocytes and sperm. Whether chemotherapy results in infertility depends on the patient’s age, the type of chemotherapeutic drugs used, and the dosage of drugs given.
Results of a recent study showed that chemotherapy-induced amenorrhea (lack of menses) is a probable risk in the first year after treatment.2 The incidence of no menses after chemotherapy in women under forty years of age ranges from 5 to 54 percent, and for those over forty years of age, it ranges from 76 to 92 percent. However, menses may return several years after treatment. The chance of return after two years of follow-up is 28 percent for those younger than forty years old and 8 percent for those over forty years of age. At age forty-five, women who undergo chemotherapy have about an 85 percent chance of going into permanent menopause. The younger the patient at the time of the treatment, the more likely she is to experience temporary amenorrhea and then resume normal menstrual function, although this can take several years. For prepubertal patients, the likelihood of early menopause and infertility is lower.
Alkylating agents, such as cyclophospamide (Cytoxan), are most harmful to oocytes. In one study, 42 percent of women treated with this type of chemotherapy were in premature menopause by the age of thirty-one, although some returned to normal menses.3 Doxorubicin (Adriamycin) and docetaxel (Taxotere) are other agents also toxic to the gonads.
Of women exposed to chemotherapy, only 5–35 percent achieve spontaneous pregnancy. Resuming normal menstrual periods does not necessarily mean that a woman is fertile. Chemotherapy can result in partial ovarian injury (decreasing the number of oocytes) such that cancer survivors have normal menstrual cycles but don’t realize they are infertile until they try to conceive. Cancer treatment may push patients out of the reproductive window and into the early stages of menopause with no particular signs or symptoms.
In men, alkylating agents are similarly most harmful to sperm production. However, the testosterone-producing cells (Leydig cells) are more resistant to chemotherapy than oocytes. Therefore, sterility may not be readily apparent. Damage to sperm production may result in low sperm count (oligozoospermia), however, with the end result of infertility. The damage caused by chemotherapy can be temporary or permanent. If the injury is directly to the sperm and does not destroy the stem cells, then recovery is possible, often with minimal residual effect. High dosages of chemotherapy can damage the Leydig cells, resulting in loss of sex drive and ejaculation and erection difficulties.
Radiation The gonads (testes or ovaries) can be temporarily or permanently damaged by radiation therapy. The severity of damaging effects is related to the radiation dosage, the number of treatments, the location of the treatment field, and the patient’s age. Radioactive iodine does not cause infertility. In contrast to chemotherapy, prepubertal age provides no protection against radiation effects to the reproductive system.
Radiation therapy affects the number of oocytes remaining in the resting pool and stem cells in the testes. The dosage that causes ovarian failure depends on age. In younger women, more oocytes are present. Therefore, at a given dosage of radiation young women have less chance of menopause than older women. In one study, radiation dosages less than 2,000 cGy resulted in ovarian failure more often in women thirteen to twenty years of age than in girls less than thirteen years old. At dosages greater than 2,000 cGy, the incidence of ovarian failure was more than 70 percent regardless of age. In women older than twenty years, dosages as low as 800 cGy can result in menopause. However, even low dosages can be harmful for both sperm and oocytes, rendering one infertile, and this result is highly unpredictable. If pelvic radiation is given at higher dosages, the uterus is also vulnerable to muscular or vascular injury.4 Symptoms include intrauterine growth retardation, spontaneous miscarriages, and preterm labor. Radiation at lower dosages to the testes may affect the sperm only, sparing the Leydig cells, yet still result in infertility. With normal supporting cells, children would experience normal pubertal development, and adults may have a normal sex drive and be capable of erections and ejaculation.
The Psychological Impact of Infertility
Infertility can be an emotionally devastating experience for anyone. In the case of cancer survivors, the possibility of infertility adds an additional burden to the many challenges created by the short- and long-term side effects of therapy and the potential for recurrence or a new cancer.
One of the domains of symbolic immortality, as described by Robert Jay Lifton, M.D., of Harvard University in his 1979 book The Broken Connection: On Death and the Continuity of Life, is the hope of leaving something behind through a biological family. Infertility often leads to grieving and loss, and although the goal of cancer therapy is survival, the possibility of being unable to continue one’s family line threatens one of the most basic dreams of life.
Patients suffering grief, loss, or anxiety may need professional counseling and psychosocial therapy to aid in psychological adjustment. The hope is that fertility may return, reinforcing the survivor’s commitment to life.
Some survivors fear having children when they are at risk for experiencing a cancer recurrence, developing a new cancer, or dying prematurely. This can cause both negative feelings and a negative approach to becoming fertile. There is also the fear that offspring conceived after cancer therapy might be born with a congenital abnormality. Thus far, a higher risk of congenital malformation is not supported by current research, which has found abnormalities in about 3.4 percent of cancer survivors’ offspring, compared with 3.1 percent of cancer-free siblings’ offspring. The genetic propensity for abnormalities in the general population is about 5 percent.5
Those fortunate enough to conceive after cancer treatment experience a greater sense of a normal life. Fertility is a high priority despite the risks, making it possible to be a parent and watch one’s progeny grow and develop, one of the most valued and coveted of life’s experiences.
Even for those who have not had cancer, infertility can be a major challenge, necessitating many physician visits, treatments, and often high costs that are not always covered by insurance. The distress from failures is an additional cost that is not always balanced by the gratification of success. Recently, there have been many advances in the treatment of infertility. If success cannot be achieved, adoption often is considered, although this approach also presents costs, both financial and emotional, in the struggle to find a suitable baby. Patients often go overseas, where more children are available for adoption, accepting the additional costs and risks of dealing with unfamiliar legal and medical systems. For many, however, adoption does not satisfy their desire to sustain the family and genetic life history.
Although a majority of infertile cancer survivors have considered adoption, another option is the third-party approach, in which a surrogate carries the baby. Alternatively, a cancer survivor may consider using a donated embryo, egg, or sperm. Some religions, such as Roman Catholicism and Islam, are against third-party reproduction. Having one’s own biological child through use of current advanced technology is becoming a potentially more accessible approach.
The improved long-term survival and cure rates for many cancers have made future fertility a question to be considered in reproductive-age patients, preferably before the cancer treatment begins. The importance of this question has been recognized, and although the existing options are limited, particularly in women, this is an area of active research, and it is likely that in the near future other options will become available.
Clearly, cancer treatment that entails surgical removal of the testes or the ovary renders the patient sterile. To preserve fertility, the most important step for those diagnosed with cancer is to discuss their concerns with their doctor. If possible, alternative treatments, such as different chemotherapeutic agents or radiation exposure, may help decrease the incidence of infertility. Before beginning treatment, discuss alternative options for fertility preservation with your doctor so that he or she can refer you to a fertility clinic. Some of the available options can be performed after treatment, but the most effective methods are used before cancer treatment.
Men Men have the option of freezing (cryopreserving) sperm for later use. This process is available in most major medical centers and is a simple and affordable method. Semen cryopreservation has been used successfully for more than fifty years. Sperm banking should be completed before the initiation of radiation therapy or chemotherapy in case the sperm count and quality do not return to normal after treatment. The sperm can be stored indefinitely without significant damage. When ready for use, the sperm are thawed and available for intrauterine insemination (IUI) or assisted reproductive techniques (ARTs). Unfortunately, men often are not advised of this option before therapy. It has been estimated that only 10–30 percent of patients use the option of stored semen.6
Men with cancer often have abnormal sperm counts before treatment. In the past, low sperm counts were a reason not to bank sperm because poor samples yield a low pregnancy rate with IUI. However, with ARTs, such as in vitro fertilization and intracytoplasmic (into egg) sperm injection, there is a high success rate for successful fertilizations and pregnancy.7
Boys and young adolescents who have not experienced puberty do not make sperm and therefore are unable to use sperm banking. For these patients, encouraging approaches in the experimental phase include the following:
• Gonadotropin-releasing hormone (GnRH) agonists: This hormonal therapy is administered by injection every month or every three months. It temporarily shuts down the reproductive system, thereby decreasing the number of dividing cells in the testes. Thus far, there are no proven studies of a GnRH agonist successfully protecting males from high-dose chemotherapy damage. Although older studies have shown no protection against chemotherapy, recent studies have suggested a possible benefit.
• Cryopreserved testicular tissue for future transplantation: Testicular tissue is obtained surgically and cryopreserved. When ready for use, the tissue is transplanted back into the testes, making spontaneous conception possible. This is an option for prepubertal patients. Research on this option is in progress, and to date there have been no live births from this method.
• Testicular sperm extraction (TESE): In men with no sperm in their ejaculate, TESE is an option. It is a well-established procedure to overcome severe male infertility and has a high pregnancy success rate. The chance of obtaining sperm is 30–70 percent. TESE may also be an option for prepubertal patients but is still in the experimental phase, with no pregnancies to date.
Options after cancer treatment depend on the severity of damage to the testes. If sperm are present, IUI and ART are available options. If there are no sperm in the ejaculate, TESE may be attempted. Hormonal therapies such as FSH and LH to increase sperm production are being investigated.
Women In women, the damage done to ovaries by cancer treatment depends on a number of factors, including the patient’s age at the time of treatment, the dosage and particular chemotherapeutic drug used, and the dosage and fractionation schedule of radiation.
For women, there are a number of strategies for preserving fertility:
• Embryo cryopreservation: The most well-established option is embryo cryopreservation. It is a common technique used with couples to overcome infertility. It is available only for women who have experienced puberty and have a partner or are willing to use donor sperm. The success rate depends on the woman’s age and the number of oocytes recovered from the ovary. The process entails a two- to six-week time commitment and should be performed before the initiation of cancer treatment. It begins with ovarian stimulation, which allows multiple oocytes to be produced. The ovarian stimulation requires FSH and LH and results in increases in estrogen production. In cases of hormone-sensitive cancer (i.e., breast cancer), techniques to reduce estrogen production are available. The oocytes are collected by a surgical procedure, using an ultrasound-guided needle that is passed through the vagina into the ovaries to collect oocytes. Once the oocytes are recovered, they are fertilized and stored for later use. When the patient is ready for pregnancy, the embryos are thawed and transferred into the uterus. In some cases, it may not be possible to delay cancer treatments long enough to do ovarian stimulation. If this procedure is desired, the patient should discuss it with her doctor as soon as possible so that the possible delay in cancer treatment is minimized.
The other options available to women are in the experimental phase and include the following:
• Egg (oocyte) cryopreservation: A question that often arises is, “Can I bank my eggs just like men can bank their sperm?” The process is similar to embryo cryopreservation. However, the oocyte is not fertilized. Therefore, the earlier need for a partner or donor sperm is avoided. Unfortunately, at present this is not routinely possible. However, in a few centers it is being performed on an experimental basis under the strict supervision of institutional research committees. The success depends on the woman’s age and the number of oocytes recovered. The reported success is 2–4 percent live births per oocyte recovered. The lower survival rate of frozen eggs after thawing and the less than optimal pregnancy yield makes freezing of ova obtained before cancer treatment not yet widely available as a clinical option. This area is of great research interest, and advancements are continually developing, with corresponding improvements in pregnancy rates, so it is likely that egg banking will be feasible in the near future.
• Ovarian transposition (oophoropexy): Oophoropexy can protect the ovaries from radiation. The operation places the ovaries out of the radiation field. This technique has been used for years to shield the ovaries from radiation during pelvic irradiation, but the results are variable for fertility protection, ranging between 0 and 90 percent.8 The variability in success is attributed to the difficulty of keeping the ovary out of the radiation field and the concurrent use of chemotherapy in addition to radiation. In the past this procedure entailed a long recovery time, thereby delaying radiation treatment. Newer oophoropexy techniques under investigation show promising results.
• Ovarian cryopreservation (tissue freezing): Another approach being studied is that of freezing ovarian tissue in the hope that later, after successful treatment of the cancer, it can be transplanted back into the patient and still function. This procedure is not widely available at this time. This process has no time requirement and therefore avoids any delay in cancer treatment. It does not require ovarian stimulation or a partner and is an option for prepubertal patients. The tissue is obtained surgically and cryopreserved. When the patient is ready, the tissue is transplanted (autotransplantation) by either of two methods:
• Orthotopic transplant: The ovarian tissue is transplanted back into the native ovaries. This process would potentially produce sex steroids, resume menstrual cycles, and allow spontaneous conception. To date, two reported live births have occurred after orthotopic transplant.
• Heterotropic transplant: The ovarian tissue is transplanted under the skin (e.g., in the arm). This process would potentially produce sex steroids and resume menstrual cycles but would not allow spontaneous conception. In order to conceive, ART would be needed. No live births to date have been recorded after heterotropic transplantation.
A major concern for ovarian transplantation is the possibility of reintroducing malignant cells from the ovarian tissue to a cancer survivor. The ovarian tissue removed before treatment could contain latent malignant cells, and cryopreservation does not kill cancer cells. Investigations are being performed to reliably screen for cancer cells in the ovarian tissue.
• GnRH analogs: This hormonal therapy is administered by injection every month or every three months. It temporarily shuts down the reproductive system, decreasing the number of dividing cells in the ovaries. Evidence suggests that GnRH agonists may be a beneficial option for postpubertal females receiving chemotherapy. The treatment should be administered before chemotherapy begins but may be beneficial even during treatment. Studies have shown that use of GnRH analogs does not protect against radiation.
• Gynecological cancer treatments that spare reproductive function: The options available depend on the type of cancer and whether it has spread to other places.
• Cervical cancer: Trachelectomy, removal of the cervix from early stage cervical cancer, takes special surgical expertise and appears to be a safe way to preserve the uterus for pregnancy.
• Uterine cancer: Hormonal treatments may treat early stages of uterine cancer.
• Ovarian cancer: Early stages may necessitate removal of only one ovary and tube.
Options after treatment include use of ARTs and surrogacy if a hysterectomy has been performed.
Pregnancy After Cancer Treatment
Follow-up studies indicate that the toxic effects of chemotherapy given to women before pregnancy do not appear to be a risk to children conceived naturally. However, animal studies suggest that natural conception within six months after treatment in females increases the chance of fetal abnormalities. In males, the only risks of fetal abnormality were found in those conceived during or immediately after chemotherapy.
Although cancer survival has continued to increase in recent years, infertility remains a major challenge for cancer survivors. Cancer patients interested in future fertility should receive appropriate psychological support and early referral to specialized fertility clinics and perinatal care services. It is important to note that there are no guarantees of preserving fertility with any of the aforementioned options. Cancer survivors unable to use their own eggs or sperm may still achieve pregnancy using donated eggs or sperm. The process of donating eggs or sperm is well established and has high pregnancy rates. The recipient has many options for donors, including various individual characteristics and genetic backgrounds.
A nonprofit organization, Fertile Hope, provides fertility resources for cancer patients and can be contacted at www.fertilehope.org, 888-994-HOPE, or by mail at 65 Broadway, Suite 603, New York, NY 10006.
1. Nieman CL, Kazer R, Brannigan RE, Zoloth LS, Chase-Lansdale PL. Cancer survivors and infertility: a review of a new problem and novel answers. J Support Oncol 2006;4(4):171–8.
2. Dr. Charles Shapiro, ASCO presentation, June 2006, Atlanta, GA.
3. Byrne J, Fears TR, Gail MH, Pee D, Connelly RR, Austin DF. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 1992;166(3):788–93.
4. Critchley HO, Wallace WH, Shalet SM, Mamtora H, Higginson J. Abdominal irradiation in childhood: the potential for pregnancy. Br J Obstet Gynaecol 1992;99(5):392–4.
5. Holmes GE. Long-term survival in childhood and adolescent cancer. Five-center study: U.S.A. Ann N Y Acad Sci 1997;824:180–9.
6. Audrins P, Holden CA, McLachlan RI, Kovacs GT. Semen storage for special purposes at Monash IVF from 1977 to 1997. Fertil Steril 1999;72(1):179–81.
7. Tournaye H, Goossens E, Verheyen G, Frederickx V, De Block G. Preserving the reproductive potential of men and boys with cancer: current concepts and future prospects. Hum Reprod Update 2004;10(6):525–32.
8. Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an underused procedure. Am J Obstet Gynecol 2003;188(2):367–70.