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by C.H. Weaver M.D. Medical Editor 11/2022

Cancer treatment with radiation or certain chemotherapy drugs can affect fertility transiently or permanently in both men and women, and infertility can cause profound anxiety and emotional strain.1,2,9,10 The extent of infertility is dependent on the type of treatment, the combination of agents, their dose levels, and patient age.

What causes infertility in women?

In women, damage to the ovaries causes reproductive problems, or infertility, and premature menopause in some.  Infertility after cancer treatment is typically a result of ovarian function impairment, either through the loss or damage of primordial follicles or damage to oocytes and granulosa cells.1,9 The number of primordial follicles is believed to be finite and is referred to as ovarian reserve. Certain chemotherapy drugs cause a substantial decrease in ovarian reserve. 

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What is sterility

Sterility is an inability of a man to fertilize an egg, or reproduce.  In men, damage to the testes, the organs that produce sperm, results in sterility. Some men regain their ability to reproduce, however recovery is very slow. Others have permanent sterility. There is no treatment for sterility. If you think you may want to have children in the future and your treatment is likely to damage sperm production, you may wish to bank, or store sperm.

What causes sterility in men?

Sterility is caused by poor function or failure of the testes, the male sex organs that produce sperm. Damage to the testes from radiation or chemotherapy is a common cause of sterility among cancer patients. Chemotherapy involves the use of drugs that destroy cells that grow rapidly, a characteristic of cancer cells. Unfortunately, chemotherapy also affects normal cells that grow rapidly, such as blood cells in the bone marrow, cells in the hair follicles, and the cells that generate sperm in the testes.

Following cancer chemotherapy most men develop low levels of sperm (oligospermia) or no sperm (azoospermia). In addition the cells in the testes that produce testosterone, called Leydig cells, may also be affected by chemotherapy, resulting in low or lack of testosterone production. These conditions may persist for long periods of time and may be permanent.

The effect of chemotherapy on the testes depends on the type of drug, dose, and schedule of treatment. Some chemotherapy drugs are more likely to cause sterility, while there tends to be a much lesser degrees of long-term toxicity with the newer forms of chemotherapy. The classes of chemotherapy drugs that are more likely to cause sterility are:

Alkylating agents: The alkylating agents (nitrogen mustard, cyclophosphamide, chlorambucil, busulfan, procarbazine) are a major cause of late-testicular toxicity. Long-term infertility due to treatment with alkylating agents may be expected in more than 50% of the patients at a cumulative dose of cyclophosphamide greater that 6 g/m2, and procarbazine greater than 4 g/m2.1 Procarbazine-containing regimens (MOPP/ABVD) result in azoospermia in the vast majority of patients.2

Platinum compounds: Platinum compounds (cisplatin, carboplatin and oxaliplatin) are a major cause of damage to the testes. Long-term infertility due to therapy may be expected in more than 50% of the patients who receive a cumulative dose of cisplatin (Platinol®) greater than 0.6 g/m2.

Radiotherapy has by far the most damaging effect on reproductive ability by affecting both the part of the brain that contributes to testosterone levels as well as the testes. The harmful effect of irradiation depends on the total dose of radiation, the area irradiated, as well as the number and size of fractions (treatments) given.

Do precision cancer medicines or targeted therapies cause infertility?

There is currently very little evidence on the effect of targeted therapies on male or female infertility.10,12Current research suggests that targeted agents have little or no effect on sperm production, except during puberty with some medications. Endocrine therapy may transiently cause infertility and bevacizumab may cause ovarian failure, likely due to its antiangiogenic effects.12,13

There are no known effects of immune checkpoint inhibitors on male or female fertility.6

Which patients are more likely to experience long term sterility

Age is a major factor that contributes whether a patient will recover reproductive function. Older patients are more likely to experience long-term sterility. Also, patients that undergo chemotherapy treatment for testicular cancer, Hodgkin’s disease, and childhood lymphomas are likely to experience long-term sterility. Men treated for acute lymphoblastic leukemia (ALL) may also experience some damage, but appear to recover their reproductive function.

Testicular cancer: Testicular cancer now has a cure rate of more than 80% with combination chemotherapy composed of cisplatin (Platinol®), etoposide, and bleomycin (Blenoxane®) (PEB). However, approximately 25% of patients have azoospermia (no sperm) for 2-5 years or more after treatment.3

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Additional research with survivors of testicular cancer reveal conflicting results regarding the impact of treatment on reproductive ability. While one study shows that 68% do exhibit testicular dysfunction,4 another study showed that release of hormones from the brain compensates for the loss of testosterone production in the testes.5 Therefore, response to treatment seems to vary between individuals.

Hodgkin’s disease: Many men with Hodgkin’s disease have testicular deficiencies prior to treatment. Researchers have found that 8% of patients had azoospermia (no sperm) and only 30% had normal sperm counts. Thus, 70% showed semen abnormalities before the onset of treatment.6

Additionally, patients with Hodgkin’s disease are treated with procarbazine-containing chemotherapy regimens that cause sterility in the vast majority.2 These regimens include: MOPP (nitrogen mustard, vincristine, prednisone) or ABVD (doxorubicin, bleomycin, vincristine, and dexamethasone.)

Survivors of Hodgkin’s disease typically progress through puberty normally. While some will have long-term testicular dysfunction as measured by LH and FSH levels, many will not experience this side effect of treatment.7

Acute lymphoblastic leukemia (ALL): Small studies have suggested that impairment of reproductive function occurs in most males receiving treatment for ALL, but almost all recover function after successful treatment.8

How is testicular damage diagnosed?

Decreased production of testosterone in the Lydig cells of the testes stimulates a part of the brain called the pituitary gland to produce two hormones: follicle stimulating hormone (FSH) and lutinizing hormone (LH). A common way to diagnose damage to the testes is to measure FSH and LH in the blood. Elevated levels of these two hormones indicate that testicular damage has occurred.

What are the symptoms of sterility?

In addition to infertility, some men may also experience loss of libido and potency. However, there does not appear to be any major systemic effect of testicular failure on general health that is comparable to premature menopause in women.

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How is sterility managed?

While there are no treatments for sterility, for some patients planning ahead can help deal with the possibility of not recovering function. If a treatment is likely to damage your sperm production and you think you may want to have children later, you may wish to “bank” some of your sperm before undergoing treatment.

Fertility Preservation Options

Patients who are interested or uncertain about their interest in fertility should be referred to a reproductive specialist before treatment is initiated to discuss their fertility preservation options. Some patients may also benefit from a referral to a psychosocial provider to help cope with distress regarding potential loss of fertility.

For Men: sperm cryopreservation is recommended for post-pubertal men before the initiation of treatment because there is a higher risk of genetic damage in sperm during active cancer treatment.3 Testicular tissue cryopreservation and reimplantation of the human testicular graft should only be done as part of a clinical trial or experimental protocol. Hormonal therapy does not preserve fertility in men.

For Women: There are several options for fertility preservation that can be used including embryo and unfertilized oocyte cryopreservation and ovarian tissue cryopreservation for future transplantation are established options. 

References

  1. Schrader M, Heicappell R, Muller M, et al. Impact of chemotherapy on male fertility. Onkologie 2001;24: 326-30.
  2. Howell SJ, Shalet SM, Testicular function following chemotherapy. Hum Reprod Update 2001; 7: 363-9.
  3. Chaudhary UB, Haldas JR. Long-term complications of chemotherapy for germ cell tumours. Drugs 2003;63:1565-77.
  4. Bokemeyer C, Berger CC, Kuczyk MA, et al. Evaluation of long-term toxicity after chemotherapy for testicular cancer Journal of Clinical Oncology 1996;14: 2923-2932.
  5. Nord CA, Fossa SD, Ellingsen D, A. et al. Treatment related impairment of Leydig cell function 10 years after unilateral testicular cancer (TC) Proc Am Soc Clin Oncol;2003;22: 390, Abstract #1567.
  6. Rueffer U, Breuer K, Josting A, et al. Male gonadal dysfunction in patients with Hodgkin’s disease prior to treatment. Ann Oncol 2001;12:1307-11.
  7. Papadakis V, Vlachopapadopoulou E, Van Syckle K, Gonadal function in young patients successfully treated for Hodgkin disease. Med Pediatr Oncol 1999;32:366-72.
  8. Giona F, Annino L, Donato P, et al. Gonadal, adrenal, androgen and thyroid functions in adults treated for acute lymphoblastic leukemia. Haematologica 1994;79:141-7.
  9. Bedoschi G, Navarro PA, Oktay K. Chemotherapy-induced damage to ovary: mechanisms and clinical impact. Future Oncol. 2016;12:2333-2344.

  10. Sood A, Cole D, Abdollah F, et al. Endocrine, sexual function, and infertility side effects of immune checkpoint inhibitor therapy for genitourinary cancers. Curr Urol Rep. 2018;19(9):68.

  11. Imai A, Ichigo S, Matsunami K, Takagi H, Kawabata I. Ovarian function following targeted anti-angiogenic therapy with bevacizumab. Mol Clin Oncol. 2017;6(6):807-810.

  12. American Cancer Society. How cancer treatments can affect fertility in women. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/fertility-and-sexual-side-effects/fertility-and-women-with-cancer/how-cancer-treatments-affect-fertility.html. Updated June 28, 2017. Accessed December 12, 2018.

  13. Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO Clinical Practice Guideline update. J Clin Oncol. 2018;36(19):1994-2001.

  14. Meistrich ML. The effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril. 2013;100(5). doi: 10.1016/j.fertnstert.2013.08.010