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.
Spermatozoa (sperm) production is the primary requirement for male fertility. Sperm develop and mature in the seminiferous tubules, located within the testes, which sit in the scrotum. There is constant production and development of sperm, making them a prime target for chemotherapy. Prior to puberty there is no sperm production, but germ cells are still present and continually reproducing, thus making them a target of chemotherapy as well. Germ cells and sperm can also be damaged by radiation, even in low doses. In some cases, this damage is reversible, but predicting which men will suffer permanent sterility is very difficult.
Another important group of cells within the testes are the Leydig cells, which are responsible for testosterone production. Without testosterone, a boy may not achieve puberty, or an adult male may experience loss of secondary sex characteristics (facial hair, mature genitals and deep voice) or abnormal sexual functioning. Leydig cells can be damaged by radiation, but are not as sensitive to it as sperm/ germ cells and thus require much higher doses to cause damage. In addition, Leydig cells are unlikely to be damaged by chemotherapy. Therefore, it is possible to have azoospermia (absence of sperm in the semen) due to damage to the germ cells, but still maintain normal sexual function because the Leydig cells are not damaged.
One other piece to the puzzle is the pituitary gland, located in the brain. This gland produces hormones (LH and FSH), which in turn stimulate sperm and testosterone production within the testes. Radiation therapy to the brain can damage the pituitary gland, ultimately affecting sperm and testosterone production.
Certain cancers can cause men to have poor sperm quality, even prior to treatment. It is estimated that about 40% of men with Hodgkin's disease and 50% of those with testicular cancer will have low sperm counts at the time of diagnosis. This does not mean that these men should not consider sperm banking, as advances in reproductive techniques (discussed later in this article) have made even poor quality specimens useful for reproduction.
It is extremely difficult to predict which men will become infertile as a result of chemotherapy treatments. The effects are dependent on the type and number of chemotherapy drugs received, as well as the cumulative dose received. The group of chemotherapies called alkalating agents are known to be the biggest offenders, but this varies based on the dose received. Table 1 addresses some common doses of chemotherapies and the likelihood of azoospermia. It is estimated that 90% of patients who receive high doses of alkalating agents will have long-term azoospermia. For those patients who have undergone stem cell transplants, 50% will have azoospermia, while the rates are as high as 80% for those who received total body irradiation (TBI) in preparation for the transplant.
In the past 15 years, numerous new chemotherapies and biologic therapies have been developed, and the effects of these agents on fertility are not yet known.
|Chemotherapy (dose to cause effect)||Known Effect on Sperm Count|
Chlorambucil (1.4 g/m2)
Cyclophosphamide (19 g/m2)
Procarbazine (4 g/m2)
Melphalan (140 mg/m2)
Cisplatin (500 mg/m2)
Prolonged or permanent azoospermia
BCNU (1 g/m2)
CCNU (500 mg/m2)
Azoospermia in adulthood if treated before puberty
Busulfan (600 mg/m2)
Ifosfamide (42 g/m2)
BCNU (300 mg/m2)
Azoospermia likely, and are often given with other highly sterilizing agents, adding to the effect
Doxorubicin (770 mg/m2)
Thiotepa (400 mg/m2)
Cytarabine (1 g/m2)
Vinblastine (50 g/m2)
Vincristine (8 g/m2)
When used alone, cause only temporary reductions in sperm count. In conjunction with above agents, may be additive in causing azoospermia
When used in conventional regimens, cause only temporary reductions in sperm count. In conjunction with above agents, may be additive in causing azoospermia
Table 1 : Adapted from Devita, VT et al, Cancer: Principles & Practice of Oncology (7 th edition) 2005.
To complicate things further, in many cases, azospermia (no sperm) or oligospermia (low sperm count) is temporary, with sperm production recovering in the months to as long as 4 years following therapy. Sperm counts do appear to be lower after chemotherapy, and there can be damage to the genetic makeup (DNA) of sperm after chemotherapy. Research has found that this damage is repaired by two years after therapy, although the exact time to repair is not known. For this reason, men are typically counseled to wait two years after therapy before fathering a child.
The likelihood of infertility after radiation depends on the dose to the testes, shielding, and fractionation (single dose vs. multiple doses). Doses as small as 0.1 Gy can result in decreased sperm counts, and doses of 1.5-4 Gy can result in permanent sterility. As previously noted, the Leydig cells (responsible for testosterone production) are less sensitive to the effects of radiation, with damage occurring at 30 Gy in mature males (20 Gy in prepubescent males).
If the testicles are not the primary radiation target, shielding can be used. This technique protects the testicle(s) from receiving radiation. Fractionation is the technique of dividing the total dose of radiation into multiple smaller doses. For most side effects, fractionation is used to lessen their severity, but in this case fractionation (multiple smaller doses) causes more damage to sperm than a larger, single radiation dose.
Total body irradiation (TBI) is a technique used for preparation for stem cell and bone marrow transplants. As the name implies, it is irradiation of the entire body. It is estimated that 80% of men who undergo TBI will have permanent azoospermia.
For those without permanent azoospermia, sperm counts are at their lowest 4-6 months after treatment. Counts typically return to their pretreatment levels 10-24 months after treatment, but can take longer in those who received higher doses.
If the cancer surgery requires the removal of both testes, fertility is affected because of the inability to produce sperm. Surgery on the prostate, bladder, urethra, or colon can result in a condition called retrograde ejaculation. In normal ejaculation, the semen is propelled through the urethra (the same tube that carries urine from the bladder), and the opening to the bladder closes off, allowing the semen to exit the penis. In retrograde ejaculation, the opening to the bladder does not close, allowing the semen to enter the bladder instead of exiting the penis. While this condition is not medically harmful, it does impair fertility.
The concern of possible birth defects caused by exposure of sperm 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 sperm can be damaged by cancer therapies, but this damage repairs itself by two years after treatment (the exact time to repair is unknown). For this reason, men are counseled to wait 2 years after therapy before fathering a child.
Cryopreservation (freezing & storage) of sperm is the only proven method of fertility preservation in men and has been around for over 50 years. For many men with cancer, sperm quality can be poor even before beginning therapy, and this was previously seen as a reason to forgo cryopreservation. In recent years, the techniques used for in-vitro fertilization (IVF) have improved greatly, and the use of intracytoplasmic sperm injection (ICSI) has proven successful even with limited number of sperm in a sample. In some cases, there is no room for delay in treatment, and the man may be limited to 1 or 2 sample collections. However, with the newer techniques this can be sufficient. Samples are best collected prior to starting therapy for cancer, but can be collected after therapy has started. In those cases where collection takes place after cancer therapy has begun, men should be aware of the possibility of genetic damage to this sperm. This damage and subsequent risk to the fetus has not been well studied, so there are no statistics on the probability of problems.
How does it work? Men are referred to the fertility center, where they receive information on the facility's policies and procedures and then sign consent forms related to storage. Semen samples are best collected through masturbation after refraining from sexual activity for 2-5 days. Additional samples should be collected with at least 48 hours between samples for optimal numbers of sperm. In men who do not have adequate sperm in their semen, sperm can be obtained by using a needle to withdraw sperm from the testicle (aspiration).
The samples are then mixed with a substance to protect them from the freezing and thawing process. They are slowly frozen to temperatures below -195 degrees Celsius and stored. When the samples are needed, they are slowly thawed to protect the sperm from damage. Successful fertilization has been achieved with samples stored for as long as 20 years. It is not known exactly how long sperm can survive the freezing process.
The cost of collection, freezing, and storage varies greatly, and if this is a consideration, it may be worth a few phone calls to obtain pricing. Prices for collection, processing, and freezing range from $80 to $500. There are then fees to store the samples, which can be charged monthly, yearly, or for a period of 1-5 years paid in advance. These fees can range from $85 - $400 per year. In some cases, insurance may cover these fees, so check with the insurance company. There is also considerable cost associated with IVF on the other end of the spectrum, but that may be a bridge to cross when you get there.
Although sperm banking is a good option for many, there are men who cannot delay treatment by a few days and there are boys treated prior to puberty who do not have this option. There are a few techniques being studied, but unfortunately, they are still in the research stage.
Testicular tissue freezing is being studied in humans and animals as a way to preserve fertility. Testicular tissue would be removed prior to the start of cancer therapy and frozen in methods similar to sperm freezing. For prepubescent boys, this tissue would be thawed and implanted in the man or thawed and grown in the laboratory after puberty, with the hope of the tissue starting to produce sperm. For mature men unable to produce sperm, this tissue may be implanted or thawed in the laboratory and sperm extracted. This technique has been successful in animals, but there have been no live human births to date. Many fertility clinics perform this technique, but men should be aware that this is purely experimental at this time. This technique costs approximately $3000, not including fees for storage and IVF or implantation to utilize the tissue or sperm.
One other method that has been tested is called 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. This did not prove true when tested in humans and sperm production did not recover after therapy in the men studied.
Although sperm cryopreservation is a reliable option for many men, it excludes the numerous childhood cancer survivors from the dream of starting a biologic family. Future research will hopefully find methods to preserve fertility in these young men. Testicular tissue cryopreservation holds great hope and will be a focus in the years to come.
Devita, VT, Hellman, S & Rosenberg, SA. Cancer: Principles & Practice of Oncology (7 th edition). Lippincott Williams & Wilkins, Philadelphia, PA 2005.
Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. Journal of Clinical Oncology 24:2917-31, 2006
Nieman CL, Kazer R, Brannigan RE, et al: Cancer survivors and infertility: a review of a new problem and novel answers. Journal of Supportive Oncology 4:171-8, 2006
Simon B, Lee SJ, Partridge AH, et al: Preserving fertility after cancer. CA: A Cancer Journal for Clinicians 55:211-28; quiz 263-4, 2005