Attempting to assess ovarian function after cancer treatments can be very challenging.  Factors to consider include:

 

  • Age at the time of chemotherapy and/or radiation
  • Cumulative dose of chemotherapy and/or radiation
  • Specific chemotherapeutic agents used
  • Current age
  • History of infertility
  • Currently menstrual patterns, and/or other symptoms, such as vasomotor symptoms

What does the literature tell us?

 

Many prior studies have looked at this issue.  However, many of these studies were retrospective, and most specifically address menstrual cycles, not fecundity. To date, there is no prospective data specifically addressing likelihood of infertility after cancer treatments.

Summary data – risk of amenorrhea

  Lo Presti et al. summarizes the literature about various common chemotherapeutic regimens and the risk of amenorrhea1.  Walshe et al. summarizes the data specifically for women with breast cancer2.

Chemotherapy for breast cancer:

One prospective, multi-center, observational study followed 466 women with breast cancer, using ‘bleeding calendars’3, 4.  They find that:

  • 41% of women experience an initial 6 month period of CIA (chemotherapy induced amenorrhea) after chemotherapy
  • Patients are more likely to ‘recover’ menses after AC or ACT compared to CMF
  • Age is a significant predictor of amenorrhea at 6, 12, and 24 months
    • Women are 25X more likely to have at least 6 months of amenorrhea if they are >40 versus <35
    • Only 11% of women age 20-34 had a 6 month period of amenorrhea, regardless of chemotherapy regimens
  • If a woman has 24 months of amenorrhea after chemotherapy, her chance of resumption of menses is:
    • 10% overall
    • 0% after CMF
    • 15-26% after AC or ACT
  • Limitations of this study include the fact that there is no info about exact doses of chemotherapy and no info about fertility (or hormone testing)
  • May be helpful when deciding when to switch from tamoxifen to aromatase inhibitors. 

Childhood Cancer Survivor Study

 

The Childhood Cancer Survivor study follows survivors of childhood cancers, comparing reproductive outcomes to their siblings5.  Some of their findings include:

  • Acute ovarian failure was more common in children who received:
    • Doses of >10 Gy radiation to the pelvis
    • Older children receiving alkylating agents or procarbazine
  • Premature menopause, defined as cessation of menses before age 40. 
    • Compared to their siblings childhood cancer survivors had a significantly higher likelihood of premature menopause (0.8% vs 8%, respectively, RR 13.2, 95% CI 3.2,53.5). 
    • Rates were higher in survivors who were older, had exposure to increasing doses of pelvic radiation, had a higher alkylating score (more agents and cumulative dose), and had a diagnosis of Hodgkin’s lymphoma. 

Models to predict premature menopause?

Prior Radiation Therapy

  • With radiation therapy, it is possible to determine the effective dose of radiation recieved by the ovaries with relative precision. Wallage et al. attempted to model the chance of premature menopause, based on the dose of radiotherapy and the woman's age6.
  • This has some limitations, namely that all women at a given age have the same residual ovarian function, that the decline in ovarian function over time can be explained with a “differential equation’, and that all ovaries will respond to radiation in a similar fashion.  There is no mention of women who continue to have menses, but have “diminished ovarian reserve” or fertility problems.  
  • To date, these results have not been validated prospectively in a cohort of women receiving radiation.
  • Nonetheless, attempting to predict premature menopause is a useful clinical tool, giving patients and providers a general estimate of the risk of radiation based on dose and age.

Adapted from Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005;62:738-44. 

Prior Chemotherapy

  • Predictive models are difficult with chemotherapeutic agents.  There are so many types of medications, protocols/combinations, dosing variations that it is impossible to estimate the dosage received by the ovary and reliably predict the degree of follicular damage.  
  • To date, there are no models for to predict ovarian reserve after chemotherapy.  

What does the presence or absence of menses indicate?

If the patient is NOT having menstrual cycles, what does this mean?

  • Evaluate for secondary amenorrhea.  It may be premature ovarian failure, but this should be confirmed with lab tests (FSH, estradiol, or AMH).  If these are normal, a full evaluation for secondary amenorrhea should be pursued.

If the patient IS having menstrual cycles, is she fertile?

  • If she is interested in conception now, consider checking markers of ovarian reserve (FSH, estradiol, antral follicle count, or AMH).
  • If she is not interested in a pregnancy now, she and her partner must use adequate contraception
    • Contraception in women with a history of a hormone sensitive cancer can be tricky.  Options include permanent sterilization (tubal ligation or vasectomy), copper IUD, or barrier contraception (condoms, etc). 
    • It is definitely possible to ovulate on SERMs or aromatase inhibitors (such as tamoxifen or letrozole).  Women need adequate contraception while taking these medications.

References

 

1.            Lo Presti A, Ruvolo G, Gancitano RA, Cittadini E. Ovarian function following radiation and chemotherapy for cancer. Eur J Obstet Gynecol Reprod Biol 2004;113 Suppl 1:S33-40.

2.            Walshe JM, Denduluri N, Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 2006;24:5769-79.

3.            Petrek JA, Naughton MJ, Case LD, Paskett ED, Naftalis EZ, Singletary SE et al. Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study. J Clin Oncol 2006;24:1045-51.

4.            Sukumvanich P, Case LD, Van Zee K, Singletary SE, Paskett ED, Petrek JA et al. Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: a prospective study. Cancer 2010;116:3102-11.

5.            Green DM, Sklar CA, Boice JD, Jr., Mulvihill JJ, Whitton JA, Stovall M et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin Oncol 2009;27:2374-81.

6.            Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005;62:738-44.

 

About the Author

Jennifer Mersereau, MD, MSCI, is an reproductive endocrinologist in the University of North Carolina's Department of Obstetrics and Gynecology. As the Director of the Fertility Preservation Program, she has extensive experience guiding patients and physicians through the oncofertility experience.

This page was last updated March 14, 2012.