Cancer, Cancer Treatments, and Male Fertility
Cancer Therapies and Their Impact on Male Fertility
Cancer is the 2nd most common cause of death in the United States trailing only heart disease. Cancer occurs when some of the body’s cells lose control of their normal growth control mechanisms and begin to grow rapidly and without constraint. The abnormal uncontrolled growth of these cells makes them dangerous, but it also makes them potentially vulnerable to certain targeted therapies, such as chemotherapy, radiation therapy, and some biological agents. Since many cancer treatments (especially the radiation and chemotherapy) target rapidly dividing cells, some normal body cells that have naturally rapid growth rates are unfortunately also impacted as “collateral damage”. Sperm precursor germ cells are among these rapidly dividing cells that are commonly damaged during cancer treatments resulting in problems with male fertility in cancer survivors.
A few facts about cancer treatment and male infertility
1) Cancer treatments can damage sperm precursor (germ) cells as well as potentially induce mutations in mature sperm cells that are present.
2) The impact of chemotherapy on male infertility depends on the type of agent, the dosages used, and each individual’s ability to withstand or repair damage from the chemotherapeutic agent.
3) The impact of radiation therapy on male infertility depends on where the radiation treatment was targeted, the dosage of radiation used, how the radiation was delivered (fractionated or given all in one acute dose), and each individual’s ability to withstand or repair damage from the chemotherapeutic agent.
4) Sperm banking should always be offered to men of reproductive age who are going to be starting cancer therapy. It is always best to try to freeze sperm prior to the start of the cancer therapy.
Two primary concerns arise regarding fertility when a man of reproductive age needs to undergo cancer treatments.
1) The impact of the cancer therapy on the man’s future ability to conceive.
2) This risk of health problems and/or genetic abnormalities in the children of cancer survivors.
Impact of Cancer and Cancer Treatments on Male Fertility Potential
Cancer is potentially detrimental to male fertility potential in two ways. First, as discussed above, cancer therapies can decrease a man’s fertility potential. The severity of the decrease in fertility depends on the type of therapy and how it is delivered, as well as each person’s individual physiologic response to the treatment. The sections below will cover in more detail the relative impacts of different types of cancer therapy on male fertility.
Even before any treatments have started, having cancer itself is also often bad for sperm. Many men suffering from cancer are found to have abnormal semen analysis testing at the time of the diagnosis of their malignancy. It is not uncommon for men to have even no sperm at all (azoospermia) before they have had any cancer treatment. This decrease in sperm production is likely a result of stress on the body as well as a by-product of the immune system’s efforts to fight the cancer.
The majority of men undergoing successful cancer therapy will eventually experience a return in their potential to establish a pregnancy, though this recovery process can take many years and may not be complete (i.e. there many be residual permanent decreases in fertility potential). Despite the fact that most cancer survivors recover their fertility potential, it is important for all men of reproductive age to consider sperm freezing prior to starting their cancer treatment, as some men do experience permanent azoospermia as a result of their therapy.
Risk of Birth Defects/Genetic Abnormalities Associated with Cancer Treatments
Higher levels of major congenital abnormalities have been noted in the children of male cancer survivors. A review of over 1.7 million children born in Denmark between 1994 and 2004 found a 17% increase in the risk of congenital abnormalities in children of male cancer survivors, and the association was strongest among men who had conceived with 2 years of their diagnosis (Stahl O. 2010). This risk was the same whether the children were conceived naturally or with the assistance of female fertility treatments such as IUI or IVF.
Chemotherapy and radiation therapies are known to induce chromosomal abnormalities (called “aneuploidy”) in the sperm of humans as well as in animal models. These elevated sperm aneuploidy rates tend to decrease over time after treatment in humans, but can persist for prolonged periods of time in some male cancer survivors. In addition, elevated sperm aneuploidy rates have been detected in male cancer patients even before starting cancer treatments, suggesting that the stress of a malignancy on the body can induce sperm genetic mutations by itself as well. Of note, the quality of general semen analysis parameters (e.g. density, motility, and morphology) do not necessarily correlate with the presence of elevated sperm aneuploidy.
Some sperm genetic abnormalities may interfere with normal egg fertilization, not even allowing a pregnancy to start. Other types of sperm genetic problems do not disrupt the ability of sperm to successfully fertilize an egg and form on embryo. However, the resulting genetically abnormal embryo has an elevated chance of not developing correctly and resulting in a miscarriage. In addition, sperm chromosomal abnormalities of the X, Y, 13, 18, and 21 chromosomes can result in viable pregnancies and the successful delivery of children, but who have genetic syndromes, such as Klinefelters, Turners, Patau, Edwards, and Downs Syndromes.
Like fertility potential, the degree of sperm aneuploidy induced in cancer survivors depends on the type of therapy, mode of delivery, and the individual patient’s physiologic response. The impact of sperm genetic abnormalities on the health of the resulting embryos (and subsequent child) can also depend on the (limited) ability of the woman’s eggs to repair some degree of sperm DNA damage.
Because of the risk of sperm aneuploidy following cancer treatments, suggestions have been made for couples to wait for between 6 to 24 months to start trying to conceive following the man’s completion of cancer therapy. The official AUA/ASRM recommendations are to avoid pregnancy for at least 12 months after finishing chemotherapy and/or radiation therapy. [Schlegal PN. FertSteril 2021]
Despite the risk for aneuploidy in the sperm of men with cancer before they have even started treatment, it is still recommended that they consider sperm cryopreservation prior to starting cancer therapy (which can induce even more genetic abnormalities). Sperm aneuploidy testing can be performed in some circumstances on frozen sperm as well, but no official guidelines for this currently exist.
Chemotherapy and sperm quality
As discussed above, most chemotherapeutic agents have a negative impact on sperm production and quality, as well as cause increased rates of sperm aneuploidy. With many agents, significant decreases in sperm density are typically seen one to two months following the beginning of cancer treatment. The chances of sperm returning to the ejaculate depend on the impact of the chemotherapy on the spermatogenic stem cells: some forms of chemotherapy temporarily suppress the production of sperm from the stem cells, while others tend to kill the stem cells outright. If the stem cells are not killed by the chemotherapeutic agents, then recovery of sperm production usually starts around twelve weeks after finishing the last cancer treatments. This recovery can be delayed in some men, who need two to five years or longer, and even up to ten years in some patients. If sperm do return following chemotherapy, sometimes the semen parameters return to baseline normal, but a significant proportion of men have permanent decreases in sperm density and quality. Some men never have sperm return following completion of chemotherapy. In these persistently azoospermic men, sperm can sometimes be found surgically, for use with IVF/ICSI.
Different types of chemotherapy each have their own specific degrees of toxicity to sperm production. The following is an (incomplete) list of chemotherapeutic agents that have been known to have the capacity to kill spermatogenic stem cells, resulting in permanent azoospermia in some men:
1) Alkylating agents (chlorambucil, nitrogen mustard, cyclophosphamide, procarbazine, melphalan, busulfan, ifosfamide, mustine, nitrosoureas)
-Approximately 90% of men receiving alkylating agents will become azoospermic within a few months of starting therapy, with variations depending on dosage and individual patient responses
2) Platinum agents (cisplatin, carboplatin, oxaliplatin, etc.)
-Cisplatin in commonly used in the treatment of testicular cancer and can target sperm germ cells, as well as the Sertoli cells (which support sperm growth) and Leydig cells (which produce testosterone)
High Risk Agents (mostly nitrogen mustard derivatives and alkylating agents)
1. Cyclophosphamide
2. Ifosfamide
3. Chlormethine
4. Busulfan
5. Melphalan
6. Procarbazine
7. Chlorambucil
Medium Risk Agents
1. Cisplatin
2. Carboplatin
3. Doxorubicin
Low Risk Agents
1. Vincristine
2. Methotrexate
3. Dactinomycin
4. Bleomycin
5. Mercaptopurine
6. Vinblastine. [Alhamam A. FertSteril 2023]
Less Gonadotoxic Chemotherapuetic Regimens
1. VAPEC-B (vincristine, Adriamycin, prednisone, etoposide, cyclophospamiade, bleomycin)
2. MACOP-B (methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin)
3. VEEP (vincristine, etoposide, epirubicin, prednisone)
More Gonadotoxic Regimens- increased risk azoospermia
1. MOPP (mechlorethamine, vincristine, procarbazine, prednisone)
2. CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone)
3. COPP (cyclophosphamide, vincristine, procarbazine, prednisone)
4. ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine)
5. ChlVPP/EVA (chlorambucin, vincristine, procarbazine, prednisone, etoposide, vinblastine, adriamycin). [Alhamam A. FertSteril 2023]
The following agents typically result in temporary decreases in sperm production by themselves. However, if they are used in combination with alkylating or platinum-based agents, they can increase stem cell toxicity even more:
1) Adriamycin
2) Thiotepa
3) Vinblastine
4) Cytosine
5) Arabinoside
The following agents typically result in temporary decreases in sperm production, and generally do not increase stem cell toxicity when used in combination with alkylating or platinum-based agents:
1) Mitoxantrone
2) Methotrexate
3) Dacarbazine
4) 5-fluorouracil
5) Vincristine
6) Taxanes
7) Bleomycin
Biologically Targeted Agents for Treatment Cancer and Their Impact on Sperm Quality
Many newer pharmacologic agents are being developed to treat cancer that work differently than the standard cytotoxic chemo drugs. There’s limited information about the impact of these newer agents on male fertility, but preliminary data indicate that most biological agents have minimal effects on sperm numbers and quality (there are a few exceptions, described below). The most common fertility-related impact seen with biological agents involves changes in hormone levels.
Examples of biological agents and their currently known fertility impacts include:
1) Tyrosine kinase inhibitors, such as imatibinib (Gleevec), sunitinib, and dasatinib. These drugs have modest or no impact on spermatogenesis, though they can decrease testosterone levels and cause gynecomastia (breast enlargement) in some patients.
2) Interferon alpha. No significant impact on male fertility has been noted.
3) Immunomodulating agents, such as alemtuzumab (Campath). No significant impact on sperm production has been seen, though they may cause reversible agglutination of sperm after around three months.
4) mTOR inhibitors, such as rapamycin and sirolimus. There is some evidence they may decrease sperm counts and testosterone levels.
5) Targeted radionuclides. These deliver radiation to certain tissues, and they can decrease sperm production if testicular tissue is affected.
Radiation Therapy for Cancer and Male Infertility
Radiation therapy uses ionizing radiation to kill rapidly dividing cancer cells. The impact of radiation therapy on spermatogenic stem cells depends on where the radiation is targeted. Head and neck radiation would be expected to have a negligible impact on sperm production (except indirectly if impacting pituitary function), as opposed to radiation therapy to the pelvis. When the testicles do receive radiation at high enough dosages, sperm counts typically experience a rapid decline starting about ten weeks after the radiation begins. A single dose of >400cGy to the testicles generally cause temporary or permanent azoospermia in most men, with an increased risk of damage seen with fractionated treatments (as opposed to a single acute dose). Complete azoospermia is typically seen at around eighteen weeks after therapy begins. In some circumstances, testosterone levels can also be decreased because of radiation damage to the Leydig cells as well.
Another distinctive characteristic of radiation is that tissue damage can evolve and worsen over the course of years in some people. In contrast with chemotherapy where semen parameters generally immediately worsen and then later improve, semen parameters following radiation therapy can continue to worsen over time in some men. As with chemotherapy, it is generally not recommended to use ejaculated or extracted sperm for at least six to twenty-four months following the conclusion of radiation therapy, because of the potential for damage to the sperm’s DNA; this could theoretically increase the chance of birth defects in the offspring.
Prostate brachytherapy is a form of therapy in which small radioactive seeds are placed directly into the prostate gland to treat prostate cancer. Short-term studies do not show a significant change in semen parameters at six months. However, studies with longer follow-up have found significant decreases in sperm counts and quality as well as increases in sperm aneuploidy up to four years and longer following brachytherapy. Radiation therapy of the prostate (with brachytherapy or with external beam radiation) can also affect the ability of the prostate and seminal vesicles to produce the healthy semen fluid that is needed for successful natural fertility.
A Review of Cancers in Men of Reproductive Age
The two most common cancers in men of reproductive age are testicular cancer and lymphoma. In 2017, a group out of France led by Dr. Louis Bujan studied a group of men who had undergone successful treatments for these 2 malignancies. Their goal was to evaluate sperm aneuploidy rates and see if they could determine a timeline in which men could safely begin trying to conceive with a minimal increased risk of passing on genetic abnormalities to their offspring. (Rives N Fertil/Steril 2017)(Martinez G Fertil/Steril 2017)
Testicular Cancer and Male infertility
Background- Testicular Cancer
At the time of diagnosis, before any treatment, 50 percent of men with testicular cancer have a low sperm count (oligospermia) and 10 percent have a total absence of sperm (azoospermia). Of men who had azoospermia when their cancer was diagnosed, approximately 40 percent will see return of some sperm to the ejaculate after the affected testicle has been removed.
Orchiectomy (surgical removal of the testicle) is the standard first-line therapy for testicular cancer. Removing one of the testicles can obviously have an impact on future sperm production, although sometimes, as described above, removing the affected testicle can improve sperm count if it was low or zero as a result of the cancer.
Following orchiectomy, radiation and/or chemotherapy are sometimes necessary to treat or prevent metastatic disease. Both radiation and chemotherapy can have a significant negative impact on sperm production as described above. Studies have shown that rates of long-term azoospermia following orchiectomy and chemotherapy range from 1%-42%. [Schlegal PN. FertSteril 2021]
Testicular Cancer Study
This study looked at 54 men successfully treated for testicular cancer. The men were divided into 3 groups depending on the type of therapy received.
1) Radiation therapy only
2) One to two cycles of chemotherapy (bleomycin, etoposide, cisplatin)
3) > 2 cycles of chemotherapy (bleomycin, etoposide, cisplatin)
The study found that the mean sperm aneuploidy rates returned to pre-treatment levels at 12 months for men with radiation therapy only, and at 24 months for men undergoing > 2 cycles of chemotherapy. The authors therefore suggested that these timeframes may be good recommended waiting times for men undergoing these 2 treatment regimens.
Caveats to the study were that there were too few men in the group receiving 1-2 cycles of chemotherapy to make solid recommendations for waiting times before trying to conceive. Also, at 24 months, 9 (56%) of patients in the >2 chemotherapy cycle group and 9 (39%) of patients in the radiation-only group still had sperm aneuploidy rates that were elevated above the levels seen in a control group of health sperm donors. The clinical significance of this persistent elevation is not known.
Of note, mean basic semen parameters (density, motility, morphology) were also recovered by 12 months in the radiation group and 24 months in the >2 chemotherapy cycle group, and these parameters did not seem to correlate with the presence of elevated rates of sperm aneuploidy.
Lymphoma and male infertility
Background- Lymphoma
Lymphomas are the 2nd most common can seen in young men of reproductive age. Lymphomas are generally categorized into 2 groups: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Treatments for lymphoma do not generally involve surgery, but rather rely on some combination of chemotherapy, radiation therapy, and monoclonal antibody treatments. 5 year survival rates for lymphoma patients are 80% for HL and 55% for NHL.
Like testicular cancer, abnormal semen parameters (density/motility/morphology) are common prior to any cancer treatment, as are elevated levels of sperm aneuploidy.
Lymphoma Study
58 patients were evaluated in the French study (45 with HL, 13 with NHL). Patients were divided into 2 groups depending on the type of chemotherapy regimen that they received:
1) ABVD- Adriamycin (also called doxorubicin), bleomycin, vinblastine, and dacarbazine
-This is the more standard treatment regimen at this time, and this regimen has lower associated gonadotoxicity. Sperm production recovers in about 90% of patients, and there are lower aneuploidy rates noted at 6-12 months after treatment compared with pre-treatment levels.
2) CHOP (Cyclophosphamide, doxorubicin, vincristine, prednisone) or MOPP (Mustargen, vincristine, procarbazine, prednisone)
-These regimens are associated with higher rates of gonadotoxicity and sperm aneuploidy levels. At 24 months following therapy, average sperm aneuploidy levels are similar to normal values, though 3-6% of men still have increased aneuploidy at 2 years.
Sperm aneuploidy rates were significantly elevated in all studies right after therapy and tended to decrease then with time. Aneuploidy rates also were elevated past the time of one spermatogenic cycles (around 10 weeks) implying that the sperm-precursor cells must have been impacted (but not killed). Of note, routine semen parameters were again not good predictors of the presence of elevated levels of sperm aneuploidy.
Recommendations from Lymphoma Study:
1) Wait to try and conceive for 2 years following treatment with CHOP/MOPP regimen and 1 year after ABVD
2) Detection of sperm aneuploidy by FISH (fluorescent in situ hybridization) studies can be performed on cryopreserved sperm (frozen before treatment) or ejaculated sperm after treatment to identify at-risk patients
3) Consider the use of IVF/ICSI + PGS (preimplantation genetic screening) and/or more intensive monitoring of pregnancy if:
a) trying to conceive <1 year following treatment with ABVD
b) trying to conceive <2 years following treatment with CHOP/MOPP
c) using sperm with increase aneuploidy rates (ejaculated or cryopreserved)
4) Consider sperm banking prior to starting chemotherapy (despite the risk of increased aneuploidy rates in these sperm)
Sperm Banking and Cancer
Ideally, men would freeze sperm prior to starting chemotherapy and radiation therapy. This does not always happen as sometimes the man is too ill to be able to provide a sample or his treatment needs to be started emergently and there is no time to get freezing coordinated with the fertility lab. Also, the stress on the body from the malignancy can also severely depress sperm production in some men who can be azoospermic even before the start of chemo/radiation treatments. However, whenever possible, it is recommended that men who are going to be starting chemotherapy and/or radiation therapy, and who like to keep their options open for having children later should try to freeze sperm. Sperm freezing should always be done prior to the first chemotherapy/radiation therapy as these treatments can induce chromosomal abnormalities in sperm which could potentially negatively impact the health of children conceived using those sperm. A more difficult situation arises when children are diagnosed with a malignancy. Spermarche usually occurs around age 13-14yrs. If boys are post-pubertal and are Tanner Stage 3 then they are likely to have sperm that can be frozen. [AUA Update Vol 37 2018] Ideally they would provide a sample by masturbation, but if this is not possible then a sperm extraction (under anesthesia) could be employed. For pre-pubertal boys, many childrens hospitals have experimental protocols involving surgical removal of testicular tissue prior tho the start of chemotherapy/radiation therapy. This tissue is frozen in the hopes that future technology will allow the stem cells within the testicular tubules to someday be able to generate usable sperm for IVF/ICSI.