Counseling a woman with breast cancer regarding fertility ideally attempts to align two goals-one for the patient and her disease, and one for the chance of a future child. Early collaboration with a reproductive specialist should enhance discussion of the most practically available fertility-promoting options.
In this issue of ONCOLOGY, Dr. Pamela Munster highlights issues regarding the complexity of managing reproductive expectations in women who have a diagnosis of breast cancer. This complexity derives from five relevant factors that influence decisions about therapy: risks of chemotherapy, quality of life, benefits of ovarian suppression, available interventions to preserve fertility, and assessment of genetic predispositions.
I would like to develop two points that underlie those five factors. One is to reinforce the author’s suggestion that early consultation with reproductive specialists be encouraged. The second is to discuss the concept of ovarian reserve and to both promote and qualify the merit of ovarian-reserve assessment in women faced with treatment protocols that may compromise ovarian function.
The need to counsel women about options for fertility preservation is important, but the actual process of timely, collaborative referral to specialists outside of oncology is exercised only in a minority of circumstances.[1-5] Surveys of treating care providers have assessed which aspects of care delivery are correlated with this discrepancy. Responses include poor prognosis for the patient, the age of the woman, whether she has had any children, and perceived inadequate time to initiate fertility therapy. Other issues like a woman’s proximity to natural menopause, the uncertain effectiveness of cotreatment with gonadotropin-releasing hormone–agonists, and the evolving contributions of assisted reproductive technology (ART) in helping women to conceive, are all relevant in any full discussion of options for fertility preservation.[7-9] Other studies discussed the impact of oncologists’ uncertainty regarding the effectiveness of fertility-promoting protocols, as well as the availability of expertise, or the perceived poor success rates of existing options. Previously acknowledged issues include the time and cost restraints associated with specific surgical suggestions or assisted-technology options.[5,7]
It is difficult to draw conclusions from the various sources of information in the literature regarding fertility-promoting options. It was noted in one retrospective survey of women with five cancer types, including breast cancer, that 61% of women were counseled by the oncology team, 5% were counseled by fertility specialists, and 4% initiated steps to preserve their fertility. A multi-institution survey of oncologists in different specialties suggested that only 33.2% and 5.8% of respondents usually or always refer patients to a reproductive specialist, respectively. Seventy-two percent of respondents to a Web-based survey of young women with breast cancer reported they had discussed fertility concerns with a doctor, and 17% had discussed the issues with a fertility specialist. What emerges from these publications is that a majority of women are interested in having the fertility-preservation discussion,[2,3] and there may be a quality-of-life benefit to the process, independent of the patient’s age or whether fertility-sparing options are actually explored.[1,4]
Treatment modalities involving chemotherapy and extended intervals of ovarian suppression, often in an adjuvant setting, predictably result in degrees of loss of ovarian function. The extent and duration of ovarian compromise for an individual woman are not entirely predictable.
When women with infertility are seen by reproductive specialists, assessing extant ovarian function is a priority. This simple truth subsumes the related points made by Dr. Munster that women treated for breast cancer are at risk for loss of ovarian function, and that a treated patient’s menstrual pattern, and the treatment goal of preserving future ovarian function as represented by maintenance of menstruation, are relevant to fertility preservation. The concept of ovarian reserve-oocyte quantity and quality-informs the clinical counseling and management of women with infertility. Women may exhibit predictable menstruation and yet have diminished reserve. However, quantifying a woman’s chance of conception by measuring specific hormones associated with ovulation is problematic. Two decades of studies have attempted to characterize ovarian reserve using specific markers, often assessing follicle-stimulating hormone, estradiol, inhibins, and anti-Mllerian hormone (AMH).[11-15]
As more studies are published that investigate the correlations of hormones with stages in a woman’s reproductive life span, AMH is emerging as a predictor of a woman’s proximity to physiologically true menopause.[14-16] Its utility as a hormone marker for ovarian reserve is becoming more accepted. The application of AMH assessment in clinical infertility is to provide some inference of a woman’s ovarian reserve; values declining below a designated threshold are associated with diminution in functional oocytes, with implications of reduced ovarian response to exogenous stimulation and lower rates of fertilization, embryo creation, and a successful pregnancy outcome of ART. The data are primarily derived from single-time-point assessments in women whose ovaries are naturally aging. The predictive utility of serial AMH measurements is still being explored.[17,18]
Whether AMH assessment in women undergoing or completing cancer treatment has utility comparable to its emerging use in reproductive medicine remains to be fully assessed. A recent publication by Anderson et al concluded that pretreatment serum AMH hormone levels predict long-term ovarian function after chemotherapy for early breast cancer. A different clinical study, examining AMH in women after ovarian transplantation, provides insight into the unreliability of low AMH determinations and fluctuating FSH levels, including those associated with two pregnancies.
To conclude, counseling a woman with breast cancer regarding fertility ideally attempts to align two goals-one for the patient and her disease, and one for the chance of a future child.[4,5] Early collaboration with a reproductive specialist should enhance discussion of the most practically available fertility-promoting options.[9,21] Probabilities of transient, diminished, or complete loss of ovarian reserve as a result of cancer therapy are hard to quantify. Ovarian reserve screening is one process by which this clinical continuum is assessed. The conclusions derived from studies in otherwise healthy women as they progress through perimenopause and menopause may not be as clinically applicable to women who resume menstruating following treatment for breast cancer, and they need to be validated.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Letourneau JM, Ebbel EE, Katz PP, et al. Pretreatment fertility counseling and fertility preservation improve quality of life in reproductive age women with cancer. Cancer. 2012;118:1710-17.
2. Scanlon M, Blaes A, Geller M, et al. Patient satisfaction with physician discussions of treatment impact on fertility, menopause and sexual health among pre-menopausal women with cancer. J Cancer. 2012;3:217-25.
3. Forman EJ, Anders CK, Behera MA. A nationwide survey of oncologists regarding treatment-related infertility and fertility preservation in female cancer patients. Fertil Steril. 2010;94:1652-6.
4. Partridge AH, Gelber S, Peppercorn J, et al. Web-based fertility survey of fertility issues in young women with breast cancer. J Clin Oncol. 2004;22:4174-83.
5. Duffy CM, Allen SM, Clark MA. Discussions regarding reproductive health for young women with breast cancer undergoing chemotherapy. J Clin Oncol. 2005;23:766-73.
6. Badawy A, Elnashar A, El-Ashry M, et al. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril. 2009;91:694-7.
7. Marhhom E, Cohen I. Fertility preservation options for women with malignancies. Obstet Gynecol Surv. 2006;62:58-72.
8. Tao T, Del Valle A. Human oocyte and ovarian tissue cryopreservation and its application. J Assist Reprod Genet. 2008;25:287-96.
9. Von Wolff M, Montag M, Dittrich R, et al. Fertility preservation in women – a practical guide to preservation techniques and therapeutic strategies in breast cancer, Hodgkin’s lymphoma and borderline ovarian tumours by the fertility preservation network FertiPROTEKT. Arch Gynecol Obstet. 2011;284:427-35.
10. Peddie VL, Porter MA, Barbour R, et al. Factors affecting decision making about fertility preservation after cancer diagnosis: a qualitative study. Br J Obstet Gynecol. 2012;119:1049-57.
11. MacNaughton J, Banah M, McCloud P, et al. Age related changes in follicle stimulating hormone, luteinizing hormone, oestradiol, and immunoreactive inhibin in women of reproductive age. Clin Endocrinol. 1992;36:339-45.
12. Blazar AS, Lambert-Messerlian G, Hackett R, et al. Use of antimÃ¼llerian hormone levels to predict cycle outcome. Am J Obstet Gynecol. 2011;205:223-4.
13. Brown JR, Hung-Ching L, Sewitch KF, et al. Variability of day 3 follicle-stimulating hormone levels in eumenorrheic women. J Reprod Med. 1995;40:620-4.
14. Sowers MR, Eyvazzadeh AD, McConnell D, et al. Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab. 2008;93:3478-83.
15. Freeman EW, Sammel MD, Lin H, et al. Contribution of the rate of change of antimÃ¼llerian hormone in estimating time to menopause for late reproductive-age women. Fertil Steril. 2012;98:1254-9.
16. Van Disseldorp J, Faddy MJ, Themmen PN, et al. Relationship of serum antimÃ¼llerian hormone concentration to age at menopause. J Clin Endocrinol Metab. 2008;93:2129-34.
17. Ledger WL. Clinical utility of measurement of anti-mÃ¼llerian hormone in reproductive endocrinology. J Clin Endocrinol Metab. 2010;95:5144-54.
18. Sowers MR, Zheng H, McConnell D, et al. Follicle stimulating hormone and its rate of change in defining menopause transition stages. J Clin Endocrinol Metab. 2008;93:3958-64.
19. Anderson RA, Cameron DA. Pretreatment serum anti-mÃ¼llerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab. 2011;96:1336-43.
20. Greve T, Schmidt KT, Kristensen SG, et al. Evaluation of the ovarian reserve in women transplanted with frozen and thawed ovarian cortical tissue. Fertil Steril. 2012;97:1394-8.
21. Forman EJ, Li X, Ferry KM, et al. Oocyte vitrification does not increase the risk of embryonic aneuploidy or diminish the implantation potential of blastocyst created after intracytoplasmic sperm injection: a novel, paired randomized controlled trial using DNA fingerprinting. Fertil Steril. 2012;98:644-9.