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Clin Exp Reprod Med > Volume 44(4); 2017 > Article
Kim, Kim, Lee, Hwang, Suh, and Kim: Fertility preservation for patients with breast cancer: The Korean Society for Fertility Preservation clinical guidelines

Abstract

With advances in the methods of cancer treatment used in modern medicine, the number of breast cancer survivors has been consistently rising. As the number of women who wish to become pregnant after being diagnosed with breast cancer increases, it is necessary to consider fertility preservation in these patients. However, medical doctors may be unaware of the importance of fertility preservation among cancer patients because most patients do not share their concerns about fertility with their doctors. Considering the time spent choosing and undergoing treatment, an early referral to a reproductive specialist is the best way to prevent a delay in cancer treatment. Since it is not easy to make decisions on matters related to cancer diagnosis and fertility, patients should be provided with enough time for decision-making, and to allow for this, an early referral will provide patients with sufficient time to choose an appropriate method of fertility preservation. The currently available options of fertility preservation for patients with breast cancer include cryopreservation of embryos, oocytes, and ovarian tissue and gonadotropin-releasing hormone agonist treatment before and during chemotherapy. An appropriate method of fertility preservation must be selected through consultations between individual patients and health professionals and analyses of the pros and cons of different options.

Introduction

With advances in the methods of cancer treatment used in modern medicine, the number of cancer survivors has been consistently rising. The Surveillance, Epidemiology, and End Results (SEER) program reported that in 2013, the incidence of breast cancer was 125 cases per 100,000 persons and that the 5-year breast cancer survival rate was 89.7% in the United States [1]. This means that the number of breast cancer survivors in the United States is approximately 3 million. In South Korea, 18,304 people were diagnosed with breast cancer in 2014, which is four times the number recorded 15 years prior. The 5-year relative survival rate was 83.2% in 1996 to 2000, and has increased to 92.0% in 2010 to 2014 [2]. With the increase in the survival rate of breast cancer, it has become important to reduce the rate of postoperative morbidities and to consider cancer survivors' quality of life. Fertility preservation is especially important in Korea, where the number of patients who develop breast cancer before menopause is considerably higher than in the United States (47.9% vs. 20.0% in women aged less than 50 years) [3,4]. We would like to discuss several issues related to fertility preservation in patients with breast cancer that may be important to consider during the treatment of these patients.

Should patients diagnosed with breast cancer be referred to fertility specialists?

One of the main concerns of young patients with cancer is whether cancer treatment will affect their fertility. However, oncologists generally remain unaware of the importance of fertility preservation among cancer patients because most patients do not share their concerns about fertility with their doctors. Patients may be too shocked upon learning of their cancer diagnosis to discuss any other matters with their doctors [5]; however, younger women with a diagnosis of breast cancer reported that they had unmet needs for fertility-or menopause-related discussions with a reproductive specialist [6]. Counseling about premature ovarian insufficiency and fertility issues is an overlooked part of the treatment plan for young premenopausal women with breast cancer [7].
Partridge et al. [8], in their study of patients with early breast cancer, reported that 57% of the patients were concerned about their future fertility upon learning of their cancer diagnosis, and 29% responded that their concerns affected their decision with regard to therapy. In addition, 51% of all patients felt that their concerns about fertility were inadequately addressed, indicating that there was insufficient communication between health professionals and the patients. Young women who are interested in fertility preservation should be referred to a fertility specialist as soon as possible, as recommended by several international guidelines [9,10,11].

What significance does early referral to fertility preservation specialists hold for patients?

Considering the time spent choosing and undergoing treatment, an early referral to a reproductive specialist is the best way to prevent a delay in cancer treatment. An early referral to a fertility specialist can reduce conflicts in decisions about fertility preservation [12].
In a study by Lee et al. [1] conducted on 93 patients with breast cancer, 35 patients were referred to a reproductive specialist before surgery and 58 after surgery. The mean time from the first diagnosis to the initiation of ovarian stimulation was 42.6 days for patients who were referred before surgery and 71.9 days for those who were referred after surgery. In addition, the mean time from the first diagnosis to the first chemotherapy session was 83.9 days for patients who were referred before surgery, and 107.8 days for those who were referred after surgery; the former were able to undergo chemotherapy much earlier than the latter (p=0.045). A significant difference in the number of patients who could afford time to undergo two cycles of fertility preservation before treatment was also found; 25.7% of patients referred before surgery and 1.7% of patients referred after surgery were able to undergo fertility preservation twice. As a result, the number of oocytes retrieved increased by 18%. Since it is not easy to make decisions on matters related to cancer diagnosis and fertility, patients should be provided with enough time for decision-making, and to allow for this, early referral to the appropriate health professionals is crucial.

The effects of chemotherapy on fertility

The ovarian dysfunction following chemotherapy in patients with malignant tumors is affected by the patient's age, ovulatory function at the time of treatment, the type of medications used, and the length of treatment. Alkylating agents such as cyclophosphamide and ifosfamide have an especially high risk for ovarian failure, while antimetabolites pose a relatively low risk [13]. The average rate of chemotherapy-related amenorrhea was 30% to 40% in in women aged less than 40 years and 76% to 95% in women aged 40 or more years after cyclophosphamide, methotrexate, and 5-fluorouracil treatment for at least 3 months [14,15]. In contrast, four cycles of anthracycline and cyclophosphamide and paclitaxel led to amenorrhea in 13.5% of women younger than 40 years, but 69.9% of women aged 40 to 49 years [16]. Furthermore, there was no difference in amenorrhea according to trastuzumab use in patients with human epidermal growth factor receptor 2-positive breast cancer [16].
In many cases, it is difficult to clearly assess the effects of chemotherapy on fertility. This is because amenorrhea does not necessarily indicate menopause and it is experienced by patients with female-hormone dependent cancer following the administration of tamoxifen, making it difficult to tell whether a patient has reached menopause or not [17,18]. Furthermore, even when a patient menstruates regularly, it cannot be concluded that chemotherapy has had no effect on her ovulatory function. All of these considerations must be taken into account when conducting research on the effects of chemotherapy on fertility and the prevention of these effects. To overcome these limitations, ovulatory function must be assessed using anti-Müllerian hormone, follicle-stimulating hormone, and ultrasonography in addition to checking the patient's menstrual status.

What options are available for patients with breast cancer who wish to preserve their fertility?

Patients with breast cancer who wish to preserve their fertility may choose to undergo oocyte or embryo cryopreservation, cryopreservation of ovarian tissue that is obtained before the administration of anticancer drugs, or suppression of the effects of anticancer drugs on the ovaries through ovarian suppression.

1. Embryo or oocyte cryopreservation

Embryo cryopreservation is the most well-established method of fertility preservation. Embryo cryopreservation follows the procedure used in infertile patients for in vitro fertilization. The ovaries are stimulated with gonadotropic hormones to acquire multiple oocytes, and then gonadotropin-releasing hormone (GnRH) agonists or antagonists are administered to inhibit early ovulation. After 30 years of being clinically practiced, in vitro fertilization has now become a standardized procedure, alongside embryo cryopreservation, which has also been widely used as a method of preserving surplus embryos. However, for in vitro fertilization, drug administration starts during the early proliferative phase of the menstrual cycle, and cancer patients may find it difficult to wait for the optimal timing. Although luteolysis has been suggested to induce early menstruation, cryopreservation is only indicated for a small number of patients.
However, since the recent discovery that follicle recruitment occurs multiple times within a single menstrual cycle [19], ovarian stimulation has been performed regardless of timing within the menstrual cycle (random-start protocol). It has also been reported that lutealphase ovarian stimulation, which was considered inadequate in the past, does not affect the number of oocytes retrieved [20,21]. Since oocyte retrieval typically takes around 2 weeks, a patient can be offered a wide variety of options for fertility preservation if she can afford 2 to 3 weeks of waiting time.
For fertility preservation in postpubertal females without a committed male partner, oocyte cryopreservation is another option for fertility preservation [22]. Even if the protocol for ovarian stimulation and oocyte retrieval in oocyte cryopreservation is similar to that of embryo cryopreservation, concerns have been articulated regarding lower implantation and pregnancy rates than those obtained with fresh or frozen embryos. However, recent studies have reported that embryo transfer cycles using frozen-thawed oocytes had comparable success rates to those using unfrozen oocytes [23,24,25]. As cryopreservation and thawing techniques have been refined recently, oocyte cryopreservation is no longer considered experimental [22].
A supraphysiologic level of estradiol during fertility preservation, including controlled ovarian stimulation (COS), might stimulate the proliferation of breast cancer cells. Therefore, a modification of conventional COS protocol has been developed to prevent this potential harm. Administration of letrozole as an aromatase inhibitor before and after ovarian stimulation seems to be a feasible option [26,27,28,29,30,31]. The co-administration of letrozole is effective in reducing the peak estradiol level without a decrease in oocyte yield [26,31]. Although definitive large-scale trials regarding the safety of COS in women with breast cancer do not yet exist, the largest prospective study [28] reported that recurrence after COS was comparable to controls and that the survival rate was not compromised. Moreover, a recent cohort study including 3,136 natural cycles and 792 letrozole cycles reported that there was no increase of major congenital malformations in women treated with letrozole for COS compared with women who underwent natural cycles [32].

2. Ovarian tissue cryopreservation

Tissue cryopreservation of the ovarian cortex seems to be an efficient way of preserving ovarian function, at least theoretically. In ovarian tissue cryopreservation, ovarian tissue is resected prior to chemotherapy, cryopreserved, and retransplanted upon treatment completion. Depending on the part of the tissue to be removed, a cortical strip or the whole ovary may be resected, and depending on the location of the transplant, orthotopic or heterotropic transplantation may be performed. More than 60 live births have been reported from ovaries cryopreserved with slow freezing or vitrification [33] though ovarian tissue cryopreservation still should be considered experimental.
During the process of freezing and thawing, ischemia of the ovarian tissue may occur, which can lead to loss of a substantial number of primordial follicles. Thus, cryopreservation and thawing by experienced hands is important, and the transplantation technique is also important for reducing ischemic damage. In patients with malignant tumors, a histologic examination or other possible tests such as polymerase chain reaction and xenotransplantation of a part of the tissue should be considered to check whether the malignant tumor has spread to the preserved ovarian tissue. Since metastasis of breast cancer to the ovary is not an extraordinary event in the course of breast cancer [34,35], patients should be informed about this probability. For patients at increased risk of ovarian cancer due to comorbid diseases closely associated with genetic mutations such as BRCA1 and BRCA2, removal of the transplanted ovarian tissue and oocyte donation can be considered upon completion of successful pregnancy and delivery.

3. Inhibition of ovarian function using GnRH agonists

The mechanism by which GnRH agonists preserve ovarian function is still not clear. Possible hypotheses are that GnRH agonists inhibit follicle-stimulating hormone secretion, shorten the ovarian and uterine cycles, inhibit the activation of GnRH receptors, and inhibit the upregulation of intragonadal antiapoptotic molecules [36]. In addition to embryo, oocyte, or ovarian tissue cryopreservation, which are performed before gonadotoxic therapy, a GnRH agonist can be used during chemotherapy. Although the effectiveness of GnRH agonists remains controversial, several studies have found that they led to a significant reduction of the risk of ovarian failure [37,38]. Moreover, a higher rate of resuming menstruation and a higher probability of pregnancy in patients undergoing GnRH agonist co-administration was demonstrated in a recent meta-analysis [39,40,41]. Although the evidence from these recent studies can be reasonably interpreted to support using a GnRH agonist during chemotherapy in women with breast cancer, GnRH agonist therapy cannot replace established methods of fertility preservation, such as embryo, oocyte, or ovarian tissue cryopreservation. Clinicians should discuss these issues with patients with breast cancer before the use of a GnRH agonist during chemotherapy.

Fertility preservation in women undergoing neoadjuvant chemotherapy

As described, oocyte or embryo cryopreservation is well established as a fertility preservation strategy, and a random-start protocol can shorten the duration of COS. However, concerns have been raised that oocyte or embryo cryopreservation might delay treatment among patients undergoing neoadjuvant chemotherapy because most of these patients have a more aggressive form of disease, making chemotherapy more urgent [42]. Although a recent small study reported that the initiation of systemic therapy was not delayed in women receiving COS before neoadjuvant chemotherapy [42], these issues of fertility preservation should be handled in an individualized manner, and the possible benefits and risks should be discussed with all women who undergo neoadjuvant chemotherapy.

Is the fertility of patients who undergo in vitro fertilization affected?

While there are concerns about reduced ovarian function in patients with cancer following in vitro fertilization, a recent study reported no significant change in ovarian function [43]. Concerns have also been raised that the increased level of estrogen after ovarian stimulation performed in preparation for in vitro fertilization may affect the prognosis of female-hormone dependent cancers, such as breast cancer. The administration of tamoxifen or an aromatase inhibitor before and after ovarian stimulation has been shown to significantly lower the level of estrogen, without affecting the fertilization rate [44] or the recurrence rate of breast cancer [45].

Conclusion

The currently available methods of fertility preservation for patients with breast cancer include cryopreservation of embryos, oocytes, and ovarian tissue and GnRH agonist treatment during chemotherapy. An appropriate method of fertility preservation must be selected based on consultations between individual patients and health professionals and analyses of the pros and cons of different options. Most importantly, patients should be promptly referred to fertility specialists upon receiving a cancer diagnosis. An early referral will allow patients sufficient time to choose an appropriate method of fertility preservation.

Notes

Conflict of interest: No potential conflict of interest relevant to this article was reported.

References

1. Lee S, Ozkavukcu S, Heytens E, Moy F, Oktay K. Value of early referral to fertility preservation in young women with breast cancer. J Clin Oncol 2010;28:4683–4686.PMID: 20876425.
crossref pmid pmc
2. National Cancer Center. Annual report of cancer statistics in Korea in 2014. Sejong: Ministry of Health and Welfare; 2016.

3. Min SY, Kim Z, Hur MH, Yoon CS, Park EH, Jung KW, et al. The basic facts of Korean breast cancer in 2013: results of a nationwide survey and breast cancer registry database. J Breast Cancer 2016;19:1–7.PMID: 27066090.
crossref pmid pmc
4. American Cancer Society. Breast cancer facts and figures 2015–2016. Atlanta: American Cancer Society; 2015.

5. Klock SC, Zhang JX, Kazer RR. Fertility preservation for female cancer patients: early clinical experience. Fertil Steril 2010;94:149–155.PMID: 19406395.
crossref pmid
6. Thewes B, Meiser B, Taylor A, Phillips KA, Pendlebury S, Capp A, et al. Fertility- and menopause-related information needs of younger women with a diagnosis of early breast cancer. J Clin Oncol 2005;23:5155–5165.PMID: 16051957.
crossref pmid
7. Duffy CM, Allen SM, Clark MA. Discussions regarding reproductive health for young women with breast cancer undergoing chemotherapy. J Clin Oncol 2005;23:766–773.PMID: 15681520.
crossref pmid
8. Partridge AH, Gelber S, Peppercorn J, Sampson E, Knudsen K, Laufer M, et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 2004;22:4174–4183.PMID: 15483028.
crossref pmid
9. Lambertini M, Del Mastro L, Pescio MC, Andersen CY, Azim HA Jr, Peccatori FA, et al. Cancer and fertility preservation: international recommendations from an expert meeting. BMC Med 2016;14:1PMID: 26728489.
crossref pmid pmc
10. Loren AW, Mangu PB, Beck LN, Brennan L, Magdalinski AJ, Partridge AH, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013;31:2500–2510.PMID: 23715580.
crossref pmid pmc
11. Munoz M, Santaballa A, Segui MA, Beato C, de la Cruz S, Espinosa J, et al. SEOM clinical guideline of fertility preservation and reproduction in cancer patients (2016). Clin Transl Oncol 2016;18:1229–1236.PMID: 27896641.
crossref pmid pmc pdf
12. Kim J, Mersereau JE. Early referral makes the decision-making about fertility preservation easier: a pilot survey study of young female cancer survivors. Support Care Cancer 2015;23:1663–1667.PMID: 25421445.
crossref pmid
13. McLaren JF, Bates GW. Fertility preservation in women of reproductive age with cancer. Am J Obstet Gynecol 2012;207:455–462.PMID: 22959764.
crossref pmid
14. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996;14:1718–1729.PMID: 8622093.
crossref pmid
15. Burstein HJ, Winer EP. Primary care for survivors of breast cancer. N Engl J Med 2000;343:1086–1094.PMID: 11027744.
crossref pmid
16. Abusief ME, Missmer SA, Ginsburg ES, Weeks JC, Partridge AH. The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer. Cancer 2010;116:791–798.PMID: 20052714.
crossref pmid
17. Berliere M, Duhoux FP, Dalenc F, Baurain JF, Dellevigne L, Galant C, et al. Tamoxifen and ovarian function. PLoS One 2013;8:e66616. PMID: 23840510.
crossref pmid pmc
18. Kim H, Han W, Ku SY, Suh CS, Kim SH, Choi YM. Feature of amenorrhea in postoperative tamoxifen users with breast cancer. J Gynecol Oncol 2017;28:e10. PMID: 27894163.
crossref pmid
19. von Wolff M, Thaler CJ, Frambach T, Zeeb C, Lawrenz B, Popovici RM, et al. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril 2009;92:1360–1365.PMID: 18930226.
crossref pmid
20. Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril 2013;100:1673–1680.PMID: 23987516.
crossref pmid
21. Kim JH, Kim SK, Lee HJ, Lee JR, Jee BC, Suh CS, et al. Efficacy of random-start controlled ovarian stimulation in cancer patients. J Korean Med Sci 2015;30:290–295.PMID: 25729252.
crossref pmid pmc
22. Ethics Committee of American Society for Reproductive Medicine. Fertility preservation and reproduction in patients facing gonadotoxic therapies: a committee opinion. Fertil Steril 2013;100:1224–1231.PMID: 24094423.
crossref pmid
23. Borini A, Lagalla C, Bonu MA, Bianchi V, Flamigni C, Coticchio G. Cumulative pregnancy rates resulting from the use of fresh and frozen oocytes: 7 years' experience. Reprod Biomed Online 2006;12:481–486.PMID: 16740222.
crossref pmid
24. Grifo JA, Noyes N. Delivery rate using cryopreserved oocytes is comparable to conventional in vitro fertilization using fresh oocytes: potential fertility preservation for female cancer patients. Fertil Steril 2010;93:391–396.PMID: 19439285.
crossref pmid
25. Kim TJ, Laufer LR, Hong SW. Vitrification of oocytes produces high pregnancy rates when carried out in fertile women. Fertil Steril 2010;93:467–474.PMID: 19217099.
crossref pmid
26. Checa Vizcaino MA, Corchado AR, Cuadri ME, Comadran MG, Brassesco M, Carreras R. The effects of letrozole on ovarian stimulation for fertility preservation in cancer-affected women. Reprod Biomed Online 2012;24:606–610.PMID: 22503276.
crossref pmid
27. Domingo J, Guillen V, Ayllon Y, Martinez M, Munoz E, Pellicer A, et al. Ovarian response to controlled ovarian hyperstimulation in cancer patients is diminished even before oncological treatment. Fertil Steril 2012;97:930–934.PMID: 22283969.
crossref pmid
28. Kim J, Turan V, Oktay K. Long-term safety of letrozole and gonadotropin stimulation for fertility preservation in women with breast cancer. J Clin Endocrinol Metab 2016;101:1364–1371.PMID: 26751194.
crossref pmid pmc
29. Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A, et al. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab 2006;91:3885–3890.PMID: 16882752.
crossref pmid pdf
30. Revelli A, Porcu E, Levi Setti PE, Delle Piane L, Merlo DF, Anserini P. Is letrozole needed for controlled ovarian stimulation in patients with estrogen receptor-positive breast cancer? Gynecol Endocrinol 2013;29:993–996.PMID: 24000936.
crossref pmid
31. Turan V, Bedoschi G, Moy F, Oktay K. Safety and feasibility of performing two consecutive ovarian stimulation cycles with the use of letrozole-gonadotropin protocol for fertility preservation in breast cancer patients. Fertil Steril 2013;100:1681–1685.e1.PMID: 24055050.
crossref pmid pmc
32. Tatsumi T, Jwa SC, Kuwahara A, Irahara M, Kubota T, Saito H. No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology. Hum Reprod 2017;32:125–132.PMID: 27821708.
crossref pmid pdf
33. Donnez J, Dolmans MM. Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice. J Assist Reprod Genet 2015;32:1167–1170.PMID: 26210678.
crossref pmid pmc
34. Bigorie V, Morice P, Duvillard P, Antoine M, Cortez A, Flejou JF, et al. Ovarian metastases from breast cancer: report of 29 cases. Cancer 2010;116:799–804.PMID: 20041486.
crossref pmid
35. Pimentel C, Becquet M, Lavoue V, Henno S, Leveque J, Ouldamer L. Ovarian metastases from breast cancer: a series of 28 cases. Anticancer Res 2016;36:4195–4200.PMID: 27466531.
pmid
36. Blumenfeld Z. How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries. Oncologist 2007;12:1044–1054.PMID: 17914074.
crossref pmid
37. Blumenfeld Z, Zur H, Dann EJ. Gonadotropin-releasing hormone agonist cotreatment during chemotherapy may increase pregnancy rate in survivors. Oncologist 2015;20:1283–1289.PMID: 26463871.
crossref pmid pmc
38. Lambertini M, Boni L, Michelotti A, Gamucci T, Scotto T, Gori S, et al. Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival: a randomized clinical trial. JAMA 2015;314:2632–2640.PMID: 26720025.
crossref pmid
39. Del Mastro L, Ceppi M, Poggio F, Bighin C, Peccatori F, Demeestere I, et al. Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Cancer Treat Rev 2014;40:675–683.PMID: 24360817.
crossref pmid
40. Lambertini M, Ceppi M, Poggio F, Peccatori FA, Azim HA Jr, Ugolini D, et al. Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies. Ann Oncol 2015;26:2408–2419.PMID: 26347105.
crossref pmid pdf
41. Munhoz RR, Pereira AA, Sasse AD, Hoff PM, Traina TA, Hudis CA, et al. Gonadotropin-releasing hormone agonists for ovarian function preservation in premenopausal women undergoing chemotherapy for early-stage breast cancer: a systematic review and meta-analysis. JAMA Oncol 2016;2:65–73.PMID: 26426573.
crossref pmid pmc
42. Chien AJ, Chambers J, Mcauley F, Kaplan T, Letourneau J, Hwang J, et al. Fertility preservation with ovarian stimulation and time to treatment in women with stage II-III breast cancer receiving neoadjuvant therapy. Breast Cancer Res Treat 2017;165:151–159.PMID: 28503722.
crossref pmid pdf
43. Quintero RB, Helmer A, Huang JQ, Westphal LM. Ovarian stimulation for fertility preservation in patients with cancer. Fertil Steril 2010;93:865–868.PMID: 19013563.
crossref pmid
44. Oktay K. An individualized approach to fertility preservation in women with cancer. J Support Oncol 2006;4:181–184.PMID: 16669460.
pmid
45. Azim AA, Costantini-Ferrando M, Oktay K. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J Clin Oncol 2008;26:2630–2635.PMID: 18509175.
crossref pmid


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