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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 4044-4046 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.9823
Measuring the Impact of Chemotherapy on Fertility in Women With Breast CancerFertility Preservation Program, Center for Reproductive Medicine and Infertility, Weill Medical College, Cornell University, New York, NY
Department of Obstetrics and Gynecology, Weill Medical College, Cornell University, New York, NY
Division of Hematology/Oncology, Department of Medicine, Weill Medical College, Cornell University, New York, NY To the Editor: In the recent article by Petrek et al1 it was shown that the menstrual impact of adjuvant chemotherapy varied depending on the type of regimen and the patient's age. While the authors should be commended for performing the largest prospective study of its kind among breast cancer survivors, their study remained limited to menstrual assessment, as has been the case in previous studies. Cessation of menstruation is the final symptom of ovarian failure (and ensuing infertility), either due to aging or chemotherapy. By the time amenorrhea occurs, women could be infertile for 5 to 10 years due to reproductive aging. Even though women continue to menstruate until their late 40s and early 50s, fertility rates drop significantly after the age of 40, with fecundity rates of nearly 0 after the age of 45.2 In contrast to what the authors argued, this infertile period can be detected by hormonal markers, even in cancer patients. Follicle stimulating hormone (FSH) and estradiol (E2) measurements on the second and third day of menstruation have been used as markers of gold standard to assess ovarian reserve and future fertility for more than a decade.3,4 While two FSH measurements of 40 mIU/mL confirms menopause, in menstruating women, an FSH measurement higher than 12 mIU (20 mIU/mL by radioimmunoassay) on the third day of menstrual period indicates severely impaired fertility.3,4 Likewise an elevated day 3 E2 higher than 75 pg/mL is also associated with low or nonexistent fertility. While this might seem paradoxical, elevated E2 levels reflect the acceleration of menstrual cycle due to high FSH levels.5 The high FSH results in an endogenous ovarian stimulation, causing ovulation to occur much earlier than the midcycle, in some cases within few days of the onset of menstruation. Moreover, because of the negative feedback from E2, FSH levels will be suppressed and can be spuriously normal. Thus, either the elevation of FSH or E2 indicates impaired fertility despite the continuation of monthly menstruation.3,4 We have recently analyzed menstrual day 3 FSH and E2 levels in eight women who were still menstruating after receiving either doxorubicin and cyclophosphamide (AC, n = 4) or AC followed by paclitaxel (n = 4) after a mean follow-up of 38 months (range, 21 to 86 months). The mean age was 40 ± 0.9 years (range, 25 to 46 years). Two of four patients who received AC plus paclitaxel, and all patients who received AC were found to have abnormally elevated day 3 FSH and/or E2 values. Petrek et al1 indicated that they determined whether monthly periods continued after chemotherapy but did not mention whether the frequency of the cycles were similar to those before the treatment. In women with diminished ovarian reserve, cycles often become shorter and less variable due to the accelerated follicle development.5 In fact the authors' observation of a paradoxical high incidence of retention of menstruation in the short term after receiving the most gonadotoxic regimen cyclophosphamide, methotrexate, and fluorouracil could be explained by this phenomenon. What baseline FSH and E2 measurements cannot do is to determine the remaining ovarian reserve before infertility develops. There are other emerging markers, such as inhibin-B and anti-Mullerian hormone (AMH), which may be more sensitive to assess the remaining reserve. Of these two, AMH appears to be the more promising marker as it is produced by earlier stage ovarian follicles, which more closely represent the ovarian reserve made up of quiescent primordial follicles.6-9 Antral follicle counts (AFC) on the third day of menstrual cycle is another promising ovarian reserve marker. Because the fraction of follicles initiating growth appear to be proportionate to the remaining ovarian reserve from histological studies, AFC have been used to predict ovarian reserve.10,11 In fact, in younger women with larger ovarian reserve, a larger number of antral follicles are visualized by ultrasound examination and there is a continual decline in AFC with age.12-14 While no studies have prospectively assessed ovarian reserve in adult cancer survivors, there have been reports on their use in survivors of childhood cancer. One study reported that despite regular menstrual cycles, survivors of childhood cancer had a smaller ovarian volume and reduced AFC and inhibin-B levels when compared with controls.15 The same authors showed that in a cancer survivor cohort that despite normal FSH levels, ovarian reserve was still reduced as evidenced by smaller ovarian volumes and lower AFC compared with age-matched controls.16 In a similar cohort of cancer survivors, investigators also found differences in AMH and FSH compared with controls.17 These preliminary reports not only indicate that it may be feasible to assess ovarian reserve in cancer patients by emerging markers such as inhibin-B, AMH, and AFC but that these markers may be more sensitive than FSH measurements alone. We have recently measured AMH levels in three breast cancer patients before and after chemotherapy (Fig 1). In all patients, AMH levels declined after each course of chemotherapy. In two patients with the ages of 36 years (received cyclophosphamide, doxorubicin, and fluorouracil/cyclophosphamide, epirubicin/fluorouracil) and 34 years (received dose dense AC), the levels fell to undetectable levels and these patients developed amenorrhea (Fig 1A and B). In the youngest patient (30 years old) who received AC, levels dropped by more than 75% after the last course of chemotherapy (Fig 1C) and that patient resumed menstruation.
It does, however, become challenging to determine fertility by FSH and E2 levels on women who are receiving tamoxifen as this agent is an ovarian stimulant.18 E2 levels can be more than 4 to 5 times elevated in women undergoing long-term tamoxifen treatment, with FSH levels suppressed due to negative feedback.19 Because of the chronic stimulation by tamoxifen, ovaries of breast cancer patients often become dysfunctional resulting in temporary menstrual abnormalities as reported by Petrek et al.1 AMH could be a potential marker to determine the ovarian reserve in these patients as the levels of this hormone are not influenced by the stage of menstrual cycle.20 Finally, Petrek et al have confirmed that age is a determinant of ovarian failure after chemotherapy and found that menstruation was maintained in women younger than 35 years of age after 3 years of follow-up, regardless of the chemotherapy regimen. Each course of chemotherapy containing cyclophosphamide will result in the loss of a fraction of ovarian reserve regardless of the patient's age.21,22 Because younger patients have a larger ovarian reserve, a larger buffer to tolerate losses, they may not experience ovarian failure in the short term after chemotherapy. However, they will experience infertility and menopause much earlier than their healthier counterparts.23 Often times young cancer patients are left with the impression that their fertility is unscathed because they remained menstruating. For the youngest patients, the least we could do is to fully inform them that their reproductive life span might have been shortened so that they can plan on childbearing earlier. Others who may not wish to have children sooner may resort to fertility preservation by a number of assisted reproductive technologies.24 For older patients who wish to have children after chemotherapy, fertility preservation procedures may always be indicated. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Petrek JA, Naughton MJ, Case LD, et al: Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: A prospective study. J Clin Oncol 24:1045-1051, 2006 2. te Velde ER, Pearson PL: The variability of female reproductive aging. Hum Reprod Update 8:141-154, 2002 3. Licciardi FL, Liu HC, Rosenwaks Z: Day 3 estradiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization. Fertil Steril 64:991-994, 1995[Medline] 4. Lutchman Singh K, Davies M, Chatterjee R: Fertility in female cancer survivors: Pathophysiology, preservation and the role of ovarian reserve testing. Hum Reprod Update 11:69-89, 2005 5. Klein NA, Battaglia DE, Fujimoto VY, et al: Reproductive aging: Accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women. J Clin Endocrinol Metab 81:1038-1045, 1996[Abstract] 6. Baarends WM, Uilenbroek JT, Kramer P, et al: Anti-Mullerian hormone and anti-Mullerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle, and gonadotropin-induced follicle growth. Endocrinology 136:4951-4962, 1995[Abstract] 7. Durlinger AL, Visser JA, Themmen AP: Regulation of ovarian function: The role of anti-Mullerian hormone. Reproduction 124:601-609, 2002[Abstract] 8. van Rooij IA, Broekmans FJ, te Velde ER, et al: Serum anti-Mullerian hormone levels: A novel measure of ovarian reserve. Hum Reprod 17:3065-3071, 2002 9. Fanchin R, Schonauer LM, Righini C, et al: Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 18:323-327, 2003 10. Gougeon A: Regulation of ovarian follicular development in primates: Facts and hypotheses. Endocr Rev 17:121-155, 1996[CrossRef][Medline] 11. Faddy MJ, Gosden RG: A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod 11:1484-1486, 1996 12. Scheffer GJ, Broekmans FJ, Bancsi LF, et al: Quantitative transvaginal two- and three-dimensional sonography of the ovaries: Reproducibility of antral follicle counts. Ultrasound Obstet Gynecol. 20:270-275, 2002[CrossRef][Medline] 13. Scheffer GJ, Broekmans FJ, Looman CW, et al: The number of antral follicles in normal women with proven fertility is the best reflection of reproductive age. Hum Reprod 18:700-706, 2003 14. Broekmans FJ, Faddy MJ, Scheffer G, et al: Antral follicle counts are related to age at natural fertility loss and age at menopause. Menopause 11:607-614, 2004[CrossRef][Medline] 15. Larsen EC, Muller J, Schmiegelow K, et al: Reduced ovarian function in long-term survivors of radiation- and chemotherapy-treated childhood cancer. J. Clin Endocrinol Metab. 88:5307-5314, 2003 16. Larsen EC, Muller J, Rechnitzer C, et al: Diminished ovarian reserve in female childhood cancer survivors with regular menstrual cycles and basal FSH <10 IU/l. Hum. Reprod 18:417-1422, 2003 17. Bath LE, Wallace WH, Shaw MP, et al: Depletion of ovarian reserve in young women after treatment for cancer in childhood: Detection by anti-Mullerian hormone, inhibin B and ovarian ultrasound. Hum Reprod 18:2368-2374, 2003 18. Oktay K, Buyuk E, Libertella N, et al: Fertility preservation in breast cancer patients: A prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 23:4347-4353, 2005 19. Klijn JGM, Beex LV, Mauriac L, et al: Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: A randomized study. J Natl Cancer Inst 92:903-911, 2000 20. Cook CL, Siow Y, Taylor S, et al: Serum mullerian-inhibiting substance levels during normal menstrual cycles. Fertil Steril 73:859-861, 2000[CrossRef][Medline] 21. Meirow D, Nugent D: The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 7:535-543, 2001 22. Sonmezer M, Oktay K: Fertility preservation in female patients. Hum Reprod Update 10:251-266, 2004 23. Byrne J, Fears TR, Gail MH, et al: Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 166:788-793, 1992[Medline] 24. Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 24:2917-2931, 2006 Related Reply
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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