help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
The Oncologist, Vol. 11, No. 5, 422-434, May 2006; doi:10.1634/theoncologist.11-5-422
© 2006 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sonmezer, M.
Right arrow Articles by Oktay, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sonmezer, M.
Right arrow Articles by Oktay, K.

Breast Cancer

Fertility Preservation in Young Women Undergoing Breast Cancer Therapy

Murat Sonmezer, Kutluk Oktay

Fertility Preservation Program, Center for Reproductive Medicine and Infertility, Department of Obstetrics and Gynecology, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York, USA

Key Words. Amenorrhea • Breast cancer • Chemotherapy • Fertility preservation

Correspondence: Kutluk Oktay, Fertility Preservation Program, Center for Reproductive Medicine and Infertility, Department of Obstetrics and Gynecology, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York, USA. Telephone: 212-746-4292; Fax: 212-746-5929; e-mail: kuo9001{at}med.cornell.edu; Web site: http://www.ivf.org

Received October 27, 2005; accepted for publication March 24, 2006.


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
 Conclusions
 Disclosure of Potential...
 References
 Additional Reading
 
After completing this course, the reader will be able to:

  1. Explain how chemotherapy for breast cancer impacts ovarian function.
  2. Discuss the incidence of ovarian failure after chemotherapy and list the chemotherapeutic agents most likely to cause loss of fertility in breast cancer patients.
  3. Describe options for fertility preservation in women undergoing breast cancer therapy.

Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
 Conclusions
 Disclosure of Potential...
 References
 Additional Reading
 
Breast cancer accounts for one third of all neoplasms seen in reproductive-age women and affects tens of thousands of women each year in that age group. The adjuvant chemotherapy regimens used for the treatment commonly affect fertility and cause premature ovarian failure. There have been recent advances in the field of fertility preservation, which can allow many of these breast cancer survivors to have children in the future. The most established option is embryo cryopreservation; oocyte cryopreservation can be considered in single women. Both of these approaches require approximately 2 weeks of ovarian stimulation beginning with the onset of the patient’s menstrual cycle. Thus, it is crucial that these patients are referred to appropriate assisted reproduction centers as soon as they are diagnosed with breast cancer. Recently developed ovarian stimulation protocols using tamoxifen and letrozole can be used to increase the margin of safety in these patients. When and if a breast cancer patient does not have time to undergo ovarian stimulation prior to chemotherapy, ovarian cryopreservation for future autotransplantation can be offered as the last resort. The benefit of ovarian protection by gonadotropin-releasing hormone analogues is unproven and unlikely, and thus this treatment should not be offered as the sole method of fertility preservation.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
 Conclusions
 Disclosure of Potential...
 References
 Additional Reading
 
Breast cancer is the most common invasive cancer in women, affecting >215,000 women annually in the U.S. and accounting for 32% of all cancers diagnosed in women [1]. Approximately 25% of breast cancer cases occur before the age of menopause, and 15% occur under the age of 45 [2–4]. The incidence of breast cancer has increased by 0.5% per year over the past decade, whereas the death rate decreased by 1.4% per year during the same period [5]. The decline in mortality is more remarkable in women aged <50 years [6]. The increase in disease-free survival (DFS) and the decrease in overall mortality are most likely a result of increased awareness of breast diseases, well-established screening programs leading to earlier detection, and better treatment, which includes more liberal use of adjuvant cytotoxic chemotherapy and hormonal therapy [6–9]. Coupled with the increase in the number of women who delay first childbirth beyond the age of 35, the use of adjuvant chemotherapy regimens has resulted in a large proportion of breast cancer patients of reproductive age facing infertility [10–12].

More than 90% of all breast cancers are diagnosed at a local or regional disease stage, with corresponding 5-year survival rates of 97% and 79%, respectively [5]. With improved cure rates from breast cancer, a greater attention has been focused on the long-term adverse effects of cytotoxic treatment that might compromise the quality of life of the survivor. The most commonly used adjuvant chemotherapy regimens use agents with a well-recognized negative impact on fertility [4, 13]. Studies have shown that reproductive concerns play an important role for young women diagnosed with breast cancer [14, 15]. In a study using a Web-based survey, 29% of women stated that infertility concerns influenced their treatment decisions [15]. In young breast cancer patients, the potential benefits of adjuvant cytotoxic treatment should be cautiously weighed against the long-term adverse impact on fertility, especially in very early-stage cancer. Many young breast cancer patients feel that their cancer physicians do not sufficiently inform them about the impact of cancer treatment on their fertility [14–16]. It is vital to provide the most up-to-date and accurate information on the effects of cancer treatment on fertility to these young women who desire greater involvement in their treatment decision making.


   THE IMPACT OF CHEMOTHERAPEUTIC AGENTS ON OVARIAN FUNCTION
Top
 Learning Objectives
 Abstract
 Introduction
 The Impact of Chemotherapeutic...
Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
 Conclusions
 Disclosure of Potential...
 References
 Additional Reading
 
The ovaries are endowed with a fixed number of resting primordial follicles at birth, which make up the ovarian reserve. In an adult ovary, primordial follicles constitute approximately 90% of the total follicle pool, each containing an oocyte arrested in prophase of the first meiotic division [17, 18]. Gonadotoxic chemotherapy causes marked follicle loss through, presumably, apoptotic cell death [19–21].

The age of the patient and cumulative dose and type of the cytotoxic agent(s) are the most important factors that determine the likelihood of gonadal failure [4, 13, 22–24] (Table 1Go). It is not clear if the duration and dose intensity of chemotherapy independently affect the risk for gonadal failure. Alkylating agents are extremely gonadotoxic because they are not cell cycle-specific and can damage resting primordial follicles, whereas cycle-specific agents such as methotrexate and 5-fluorouracil do not have any effect on ovarian reserve. In a mouse study, cyclophosphamide induced follicular damage in a dose-dependent manner through a dose range of 20–100 mg/kg, whereas destruction of primordial follicles occurred even at the lowest cyclophosphamide dose [24]. With each additional dose of cyclophosphamide administration, an incremental number of primordial follicles are lost and the incidence of ovarian failure increases. Patients who receive cyclophosphamide have a 4- to 9.3-fold greater risk for the development of premature ovarian failure than healthy controls [25, 26].


View this table:
[in this window]
[in a new window]
  		Table 1. The degree of gonadal failure associated with chemotherapeutic agents

 
One of the major weaknesses of preexisting studies assessing the impact of chemotherapy given for breast cancer on fertility is the use of chemotherapy-induced amenorrhea as a surrogate marker for infertility [4, 13, 27–29]. Transient menstrual irregularity or amenorrhea is highly likely to occur in many women during chemotherapy, and a proportion of these patients typically will resume menstruation within 6 months of completion of chemotherapy [4, 30–32]. In a previous report among patients who became amenorrheic after chemotherapy, while <11% aged >40 years resumed menses, 22%–56% of those aged <40 years regained menstruation during follow-up [4]. This is a result of the fact that developing follicles with the main source of steroid production are invariably damaged during the treatment, and it takes 3–6 months to regrow these follicles from the remaining primordial follicles. As amenorrhea is the last event to occur in the scheme of menopausal transition and as many women with diminished ovarian reserve still menstruate regularly, these studies greatly underestimate the extent of the damage. Nevertheless, because no large study with biochemical ovarian reserve assessment is available, we currently base our risk evaluation on the likelihood of amenorrhea after each chemotherapy agent or regimen.

On the flip side, resumption of menstruation after chemotherapy does not mean that fertility has been preserved. In a study reported by Schmidt et al. [33], five of the eight women with breast cancer who were treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) had undetectable inhibin B levels (as a moderately sensitive marker of ovarian reserve) despite having regular or irregular menstrual periods. It has been commonly misperceived that young women are spared from the impact of chemotherapy on their ovarian reserve. This stems from the observation that the incidence of immediate amenorrhea is lower in younger women. Because young women have a larger primordial follicle pool, they are less likely to lose all their reserve immediately, but because they have lost a significant proportion of it, they will eventually experience premature ovarian failure [34–38]. On the other hand, permanent gonadal damage can be induced with smaller doses of the implicated chemotherapeutic agents in older women with lower primordial follicle reserve. Thus, even in a women who resumes regular menstruation postchemotherapy, based on pediatric data, the incidence of infertility and premature ovarian failure is extremely high [25, 39].

Ovarian failure is diagnosed by at least two measurements of follicle-stimulating hormone (FSH) above 40 mIU/ml, regardless of menstrual bleeding. Continuation of menstruation is not a reliable indication of ovarian function and fertility, as pregnancy rates are extremely low when FSH measurements on the second or third day of the menstrual period exceed 12 mIU/ml (20 mIU/ml by radio-immunoassay) [40]. Likewise, elevation of estradiol levels above 75 pg/ml on the second or third day of the menstrual period is also associated with compromised fertility [41].

The Incidence of Ovarian Failure Following Adjuvant Chemotherapy for Breast Cancer
The reported incidence of chemotherapy-induced amenorrhea with polyagent chemotherapy for breast cancer varies widely, mostly because of nonuniformity of the definition of amenorrhea or menopause as well as variations in age distribution, treatment regimen, and duration of follow-up [4, 13, 42–45].

The incidence of chemotherapy-induced amenorrhea was reported as 68% with classic oral CMF [4, 46]. One cycle of CMF caused loss of ovarian function in ~30% of the patients [47]. Bines et al. [4] reported that adjuvant therapy with CMF caused ovarian failure in 40% of women <40 years of age and 76% of those >40 years of age (Table 2Go). In another study, the risk for menopause was 5%–40% in a 40-year-old woman and 20%–100% in a 50-year-old woman receiving CMF or CEF [13]. In a National Cancer Institute of Canada adjuvant trial, CEF was found to cause amenorrhea in 51% of the patients, whereas CMF caused amenorrhea in 42.6% [27].


View this table:
[in this window]
[in a new window]
  		Table 2. The degree of gonadotoxicity related to the most commonly used chemotherapy regimens in breast cancer; selected trials are summarized

 
Overall, the incidence of amenorrhea is in the range of 0%–96% with anthracycline-based regimens [47–49]. It was demonstrated that none of the patients <30 years of age receiving doxorubicin-containing regimens stopped menstruating during the course of chemotherapy, whereas 33% of the women aged 30–39 years and 96% of those aged 40–49 years experienced amenorrhea [49]. Even though ovarian toxicity was demonstrated in animal studies, current data are sparse in humans regarding the use of taxanes. In a retrospective analysis, doxorubicin and cyclophosphamide (AC) or AC plus paclitaxel chemotherapy induced amenorrhea in none of the women aged <35 years (n = 11), 14% of those aged 35–39 years (n = 14), 39% of those aged 40–44 years (n = 18), and all women aged 45–50 years (n = 17) [28]. The same authors concluded that the addition of paclitaxel did not substantially increase the risk for amenorrhea. In contrast, results from the Breast Cancer International Research Group (BCIRG) 01 trial showed that the incidence of amenorrhea was higher in the docetaxel, doxorubicin, and cyclophosphamide (TAC) arm compared with the fluorouracil, doxorubicin, and cyclophosphamide (FAC) arm (51.4% vs. 32.8%, respectively) [29]. Moreover, our recent data also revealed a higher incidence of amenorrhea when paclitaxel was added to anthracycline-based regimens [50]. Even though the recent data indicate that paclitaxel is at least moderately gonadotoxic, future studies are required to verify this assumption. Tamoxifen does not cause a loss in primordial follicles in reproductive age women, but its use is associated with a 5-year delay in pregnancy [51]. This delay can then result in ovarian failure, if it has not already been experienced, as the ovarian reserves of these patients have been compromised by adjuvant chemotherapy.

Use of Nongonadotoxic Ovarian Suppression Regimens as Adjuvant Treatment
Ovarian suppression has been under investigation in place of or in addition to adjuvant chemotherapy for young patients with newly diagnosed hormone-sensitive, early stage breast cancer [52–54]. In a large study comparing the efficacy and tolerability of monthly goserelin treatment for 2 years (n = 817) with CMF (n = 823), goserelin produced a similar DFS to that seen with CMF in estrogen receptor-positive patients after a median follow-up of 6 years [55]. In contrast, goserelin was found to be inferior to CMF in estrogen receptor-negative patients. Of note, 22.6% of the patients receiving goserelin were amenorrheic, as opposed to 77% who received CMF, at 3 years. In another study, nearly half of the patients with early-stage breast cancer considered adjuvant endocrine therapy worthwhile for an absolute gain in survival of 2% from a baseline of either 65% or 85% [52]. It was stated in the National Institutes of Health Consensus Statement of Adjuvant Therapy for Breast Cancer that ovarian ablation with a gonadotropin-releasing hormone agonist (GnRHa) produces results similar to those of some chemotherapy regimens [56]. An International Consensus Panel during the St. Gallen Conference recommended ovarian suppression with or without tamoxifen for hormone receptor-positive, node-negative breast cancer patients having medium- or high-risk disease, and ovarian ablation in conjunction with tamoxifen for patients with node-positive disease [57]. As a result, ovarian ablation appears to be a promising alternative to adjuvant chemotherapy for selected young breast cancer patients who desire to maximize their future chances for childbearing.

Is There a Protective Role of GnRH Analogues Against Chemotherapy-Induced Gonadal Damage?
It has been highly debated whether cotreatment with a GnRHa can prevent chemotherapy- or radiotherapy-induced gonadal damage. Studies in monkeys showed a protective role of GnRHa cotreatment against chemotherapy-induced follicle loss; however, these studies failed to demonstrate any benefit against radiotherapy-induced gonadal damage [58, 59]. In a recent mouse study, ovarian suppression by either a GnRHa or oral contraceptive did not prove effective against cyclophosphamide-induced ovarian damage [60]. There is a limited number of prospective studies in humans, which are flawed because of short-term follow-up and/or because of a lack of control subjects [61–64].

In the only prospective randomized study, including 30 men and 18 women receiving chemotherapy for Hodgkin’s disease, GnRHa treatment was demonstrated to be ineffective in preserving fertility as judged by sperm count and menstrual function [65]. Patients were randomly assigned to receive buserelin (20 men and 8 women) prior to and for the duration of cytotoxic chemotherapy. After 3 years of follow-up, all men in both the study and control groups became oligo/azospermic, while four of the eight women treated with a GnRHa and six of the nine female controls became amenorrheic. In another study, the protective role of goserelin given monthly for 1 year as adjuvant therapy was investigated in 64 premenopausal patients with early breast cancer [63]. Eighteen patients received CMF and 46 patients received an anthracycline-based regimen. Nine patients received high-dose chemotherapy and underwent autologous peripheral blood progenitor cell transplantation, and 80% of the patients were irradiated. After a median follow-up of 55 months, 86% of the patients resumed normal menses. There was no control group. Blumenfeld et al. [61] administered a GnRHa concurrently with chemotherapy in 18 women with Hodgkin’s or non-Hodgkin’s lymphomas. The study group was compared with a historical control group of 18 women treated with similar regimens. The percentage of patients resuming spontaneous ovulation and menses was significantly higher in the study group than in the control group (93.7% vs. 37%); however, the mean follow-up was only 1.7 ± 1.0 years in the study group, compared with 7.0 ± 4.9 years in the control group. In a similar study, a GnRHa appeared to be beneficial in both cancer patients (n = 54) and noncancer patients (n = 8) receiving chemotherapy [66]. The control group (n = 55) was chosen retrospectively from patients who were treated with similar regimens. The percentage of patients who resumed menses and ovulation was significantly higher in the study group than in the control group (~all vs. <50%). However, the length of follow-up was not stated for the treatment group. Based on these findings, one cannot conclude whether the lower incidence of ovarian failure was a result of GnRHa treatment or a shorter follow-up. None of these studies tested whether fertility, not just menstrual function, was preserved. In a recent abstract by Fox et al. [67], whereas GnRHa treatment appeared to reduce the incidence of amenorrhea in a population of relatively older reproductive-age women, reproductive outcome was very poor. Twenty-three of the 24 women resumed menstruation after receiving a GnRHa along with chemotherapy, and went on to attempt to conceive. Six pregnancies occurred in five patients; three resulted in miscarriage, one was terminated because of Down’s syndrome, one pregnancy was ongoing, and one delivered [67]. The protective role of GnRH antagonists has also been investigated in rodents. One study reported that the degree of protection achieved by the antagonists is dose dependent, with a lower efficiency when larger doses of cyclophosphamide were used [68]. In contrast, others suggested that GnRH antagonists might deplete ovarian follicles through a direct effect on the ovary in a murine model [69].

In addition to the lack of consistent support from clinical studies, there is currently no biological explanation for how a GnRHa can affect ovarian reserve. Primordial follicles do not express FSH or GnRH-I receptors. A GnRHa, in essence, returns the hormonal milieu to the prepubertal state. A clinical example for why gonadal suppression may not protect ovaries is the fact that prepubertal children receiving high-dose chemotherapy given before hematopoietic stem cell transplantation still suffer from ovarian failure [37]. Nevertheless, because younger patients have a larger ovarian reserve, they might tolerate some loss in the follicular pool, and immediate ovarian function might not be affected in the short term. All patients who receive high-dose gonadotoxic chemotherapy will eventually suffer from premature ovarian failure [70, 71]. In the absence of a prospective randomized study with sufficient power, we do not rely on ovarian suppression as an effective means of fertility preservation.


   ASSISTED REPRODUCTION TECHNIQUES TO PRESERVE FERTILITY IN BREAST CANCER PATIENTS
Top
 Learning Objectives
 Abstract
 Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
Cryopreservation of Ovarian...
 Future Directions
 Conclusions
 Disclosure of Potential...
 References
 Additional Reading
 
Considering the relative increase in the incidence of breast cancer coupled with the trend to delay childbearing, an escalating number of women with breast cancer will be seeking help to prevent and treat chemotherapy-induced infertility using assisted reproductive technologies (ARTs). The current options range from clinically well-established, routinely used techniques such as embryo cryopreservation to experimental ones, such as oocyte or ovarian tissue cryopreservation. A typical in vitro fertilization (IVF) cycle includes approximately 10–14 days of ovarian stimulation with gonadotropins following pituitary downregulation using GnRH analogs in order to achieve multifollicular development. A conventional IVF cycle almost always results in a supraphysiological estradiol level that may be as high as 10- to 15-fold greater than that of a natural cycle. Because conventional ovarian stimulation regimens result in a surge in estradiol levels, they are typically avoided in women with breast cancer [72, 73]. Ovulation induction regimens incorporating tamoxifen and aromatase inhibitors have been put to use [12, 74]. Below, we review the currently available, as well as experimental, techniques to preserve fertility in breast cancer patients and propose a case-based strategy to determine the most appropriate technique for individual patients (Fig. 1Go).


Figure 1
View larger version (23K):
[in this window]
[in a new window]
  		Figure 1. A proposed algorhythmic approach to decision making for fertility preservation in breast cancer patients. Embryo cryopreservation using letrozole is a novel stimulation protocol in breast cancer patients, and long-term follow-up data are awaited. Abbreviations: Cryo, cryopreservation; FP, fertility preservation; TMX, tamoxifen. Ovarian tissue and oocyte cryopreservation are experimental technologies.

 
Embryo Cryopreservation
Embryo cryopreservation has been used for more than two decades to store excess embryos and to avoid the risk for ovarian hyperstimulation after IVF [75]. The success rate of an IVF cycle using frozen-thawed embryos now approaches those with fresh embryos, and this has become a routine tool that is being used by many ART laboratories throughout the world [76, 77]. Survival rates per thawed embryos are in the range of 35%–90%, implantation rates are in the range of 8%–30%, and cumulative pregnancy rates exceed 60% [23]. If the patient has a partner and sufficient time prior to cytotoxic treatment, embryos generated through IVF can be cryopreserved and stored for future use. Because adjuvant chemotherapy is commonly initiated 4–6 weeks after surgery, there is usually adequate time to perform ovarian stimulation and IVF. Oocyte retrieval and embryo freezing can also be performed without ovarian stimulation; however, the embryo yield is low and typically no more than a single embryo can be generated [74, 78]. Because the effectiveness of IVF diminishes with every round of chemotherapy and because there is a potential for fertilizing a genetically damaged growing oocyte, it is also not recommended to perform IVF after chemotherapy is initiated [79, 80].

Epidemiological and experimental evidence suggests that estrogen plays a significant role in tumorigenesis of breast tissue. Estrogen exposure stimulates mitotic activity in mammary epithelium [72, 73, 81]. Ovarian stimulation increases the number of follicles recruited to grow and increases estrogen production in proportion to the number of follicles recruited. As a result, estrogen can reach levels 10-fold or more higher than those in a natural cycle [82–84]

Ovulation Induction with Tamoxifen in Breast Cancer
Tamoxifen, a selective estrogen modulator with antiestrogenic actions on breast tissue, is an important part of the adjuvant therapy for early-stage, hormone-sensitive breast cancer. Tamoxifen, a nonsteroidal triphenylethylene antiestrogen, was originally developed as a contraceptive agent in the United Kingdom but was later found to stimulate follicle growth [85–87]. Recently, it has been proven to be effective for chemoprevention of breast cancer [88, 89]. Clomiphene, a related compound of tamoxifen, has been used for ovulation induction for almost more four decades [90]. Tamoxifen was tested as an ovulation induction agent and proved to be as effective as clomiphene for the treatment of patients with anovulatory infertility [91].

Exploiting its dual action as an antineoplastic agent and an ovarian-stimulating drug, albeit data are limited, we recently demonstrated that tamoxifen can be safely used to perform ovarian stimulation and IVF in breast cancer patients [74]. In order to increase embryo yield, 12 women (15 cycles) with breast cancer were stimulated with 40–60 mg of tamoxifen for a mean duration of 6.9 days, beginning on day 2–3 of the menstrual cycle. Patients underwent IVF and embryo transfer (TamIVF) with either fresh (six cycles) or cryopreserved (nine cycles) embryos, and were compared with a retrospective control group of breast cancer patients who had natural cycle in vitro fertilization (NCIVF). Cycle cancellation was significantly less in patients receiving tamoxifen than in those who underwent NCIVF (1/15 vs. 4/9 patients). In the tamoxifen group, the mean peak estradiol level on the day of human chorionic gonadotropin (hCG) administration was significantly higher than in those who underwent NCIVF (442.4 pg/ml vs. 278 pg/ml). The total number of mature oocytes (1.6 ± 0.3 vs. 0.7 ± 0.2; p = .03) and total number of embryos (1.6 ± 0.3 vs. 0.6 ± 0.2; p = .02) were higher in the tamoxifen group than in the NCIVF group. As a result, TamIVF resulted in the generation of an embryo in every patient (12/12), whereas only three of five patients had an embryo following NCIVF. To prevent patients from spontaneously ovulating prior to egg retrieval, short-acting GnRH antagonists were also administered until the day of hCG administration.

Studies with tamoxifen demonstrated that its short-term use for ovulation induction does not adversely affect oocyte and embryo development [92]. Moreover, no detrimental effect on fetal development was demonstrated [93]. One study showed lower miscarriage rates with tamoxifen than with clomiphene [94]. One can question whether increased estradiol levels as a result of ovarian stimulation with tamoxifen have any detrimental effects on breast cancer. Even though tamoxifen results in an increase in estradiol levels, it also blocks the effects of supraphysiological levels of estrogen on breast tissue and inhibits the growth of breast tumors by competitive antagonism of estrogen at its receptor site. In fact, mean estradiol levels are chronically elevated in breast cancer patients on long-term tamoxifen treatment and can be higher than the levels seen in patients undergoing ovarian stimulation with tamoxifen [95, 96].

Ovulation Induction with Aromatase Inhibitors
Aromatase, which is a cytochrome P450 enzyme, catalyses the reaction that converts androgens to estrogens. Aromatase is the rate-limiting step in estrogen synthesis that reduces the amount of estrogen required for estrogen receptor-mediated transcription [97]. Letrozole, which is a third-generation aromatase inhibitor, was developed in the early 1990s. It is a potent and highly selective inhibitor of aromatase that competitively binds the active site of the enzyme [98]. Letrozole significantly suppresses plasma estradiol, estrone, and estrone sulfate levels at doses in the range of 0.1–5 mg/day, and it was recently shown to be superior to tamoxifen in the treatment of advanced-stage postmenopausal breast cancer [99, 100]. It was also demonstrated to improve DFS after completion of standard tamoxifen therapy [101]. Letrozole, in contrast to tamoxifen, which acts as a partial estrogen agonist, is not associated with an increased incidence of uterine cancer and venous thromboembolism in long-term use [9, 102].

Aromatase inhibitors have recently been tested as ovulation induction agents. Clinical studies have shown their benefit in ovulation induction alone or in combination with FSH. In poor responders, letrozole was shown to improve ovarian response to gonadotropin stimulation, and to increase the number of preovulatory follicles while decreasing gonadotropin requirement [103, 104]. Aromatase inhibitors can augment the response to ovulation induction, acting both centrally, by blocking negative feedback of estradiol on the pituitary and hypothalamus, and peripherally, by improving follicular sensitivity to gonadotropins. A possible advantage of ovarian stimulation with aromatase inhibitors in breast cancer patients is that the peak estradiol levels are lower than those with conventional stimulation regimens and minimally elevated compared with peak estradiol levels in unstimulated cycles [12, 104].

In a prospective controlled study, we demonstrated that the combination of low-dose FSH with letrozole (Letrozole-IVF) or tamoxifen (TamFSH-IVF) produced a higher embryo yield than with tamoxifen alone (Tam-IVF) [12]. Peak estradiol levels were lower with Letrozole-IVF and Tam-IVF than with TamFSH-IVF (380 ± 57, 419 ± 39, and 1,182 ± 271 pg/ml, respectively). The mean estradiol levels in the Letrozole-IVF and Tam-IVF groups were only slightly higher than those seen in natural cycles, which can be as high as 300–350 pg/ml [74]. The mean durations of follow-up were 609 days, 418 days, 272 days, and 660 days for Tam-IVF, TamFSH-IVF, Letrozole-IVF, and the control groups, respectively, and no difference was observed in recurrence rates between IVF and control patients. When compared with standard IVF cycles performed on non-cancer patients, the numbers of oocytes and embryos were lower in the Tam-IVF and TamFSH-IVF groups, whereas they were similar to those with Letrozole-IVF. While the incidence of breast cancer recurrence was approximately 10% in the control and tamoxifen-treated patients, and follow-up was short, no recurrences occurred in the letrozole-treated patients. Because the Letrozole-IVF protocol, in which letrozole and FSH are used together, results in lower estradiol levels with the highest oocyte recovery, and because of its safety profile, we currently prefer this protocol in most breast cancer patients undergoing IVF for embryo or oocyte cryopreservation. Moreover, several live births have already occurred as a result of letrozole-FSH stimulation in patients with breast cancer [105].

It must be emphasized that aromatase inhibitors should not be used during pregnancy because estradiol and its precursors can play a role in fetal development. However, there is no evidence that the exposure of oocytes to letrozole can increase birth defects. When used for in vitro fertilization, embryos are never exposed to systemic letrozole. Even when letrozole is used to assist women to conceive with unfrozen embryos, letrozole has been cleared from the circulation by the time the embryos are transferred. Moreover, a recent study on aromatase-overexpressing mice showed that when these animals were treated with high doses of letrozole for 6 weeks and allowed to conceive 2 weeks later, there was no difference between treated and control animals in terms of litter size, birth weight, and anomalies [106]. Likewise, in vitro exposure of mouse follicles to another aromatase inhibitor, anastrozole, did not increase meiotic spindle defects in oocytes and birth anomalies [107].

Oocyte Cryopreservation
When embryo cryopreservation is not feasible, oocytes can be frozen unfertilized. Ovarian stimulation is required, similar to that in IVF cycles for embryo freezing. Unfortunately, oocyte freezing is technically more challenging because of the complex structure of the human oocyte. In a recent meta-analysis, we found that the live birth rate per injected oocytes was approximately 2% for the most commonly used slow-freezing technique [108]. Pregnancy rates were one third to one fourth of the success rates seen with unfrozen oocytes. Thus, we resort to oocyte cryopreservation when embryo freezing cannot be performed, especially in single women who do not wish to use donor sperm for in vitro fertilization.


   CRYOPRESERVATION OF OVARIAN TISSUE
Top
 Learning Objectives
 Abstract
 Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
Future Directions
 Conclusions
 Disclosure of Potential...
 References
 Additional Reading
 
In ovarian cryopreservation, the cortex, which contains a rich reserve of primordial follicles, is frozen in thin slices. The success of this procedure is based on the evidence that primordial follicles are less vulnerable to cryodamage because of a high surface–volume ratio, low metabolic rate, and the absence of zona pellucida.

After the first animal trials of ovarian tissue cryopreservation in the 1950s with glycerol, 40 years have passed to achieve successful birth in animals with the discovery of modern cryoprotectants [109–111]. In humans, resumption of endocrine function has been reported after orthotopic [33, 112, 113] and heterotopic [114, 115] transplantation of frozen-thawed ovarian cortical strips. Recently, an embryo was generated from oocytes retrieved from s.c. transplanted ovarian tissue in a breast cancer survivor [116]. Most recently, two live births were reported after orthotopic transplantation of frozen-banked ovarian tissue in lymphoma survivors [117, 118].

In the orthotopic transplantation technique, frozen-thawed ovarian cortical pieces can be grafted near the infundibulopelvic ligament or on a postmenopausal ovary. In the heterotopic transplantation method, the tissue is grafted s.c. to the forearm or suprapubic area. The advantage of orthotopic transplantation is that natural conception is possible. However, this technique requires general anesthesia. Heterotopic transplantation does not require general anesthesia or abdominal surgery. It is also easy to monitor follicle development, and to remove the transplanted tissue from the s.c. site when necessary.

One of the major concerns in transplanting ovarian tissue from cancer patients is the risk for reseeding cancer cells. In breast cancer, occult ovarian involvement is rare, especially if there is no systemic metastasis and if the pelvic and ultrasound examinations are normal [119]. Previous studies showed that most of the occult metastases belong to the infiltrating lobular histological subtype, which constitutes <15% of all breast cancers and more commonly occurs in postmenopausal women [119–124]. Thus, early-stage breast cancer is not a contraindication to perform ovarian tissue cryopreservation and transplantation. However, prior to ovarian transplantation, a thorough histological assessment of a representative piece is required to rule out occult metastasis. In addition, patients with BRCA-1 and BRCA-2 genes are at a higher risk for harboring occult ovarian cancer [125]. Even though ovarian cancer is rare prior to the age of 35, these patients should be counseled about the risk [126]. There have been no reports of cancer recurrence in the limited number of cases published in the medical literature, but ovarian cryopreservation and transplantation remains an investigational protocol.

Donor Eggs and Surrogacy
IVF with donor eggs is another alternative when a cancer survivor suffers from premature menopause or low ovarian reserve as a result of cancer treatment. The success rates with appropriate egg donors may exceed 60% per embryo transfer. Patients with breast cancer who are considered at high risk for recurrence or who have to be on life-long therapy with tamoxifen or aromatase inhibitors may also resort to gestational surrogacy. However, the laws and regulations regarding this procedure vary substantially among countries and among individual states in the U.S.


   FUTURE DIRECTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
Conclusions
 Disclosure of Potential...
 References
 Additional Reading
 
Cryopreservation of the ovary as a whole with its vascular supply might help decrease the rate of follicle loss during the initial ischemia period [127]. Currently, there is no optimum cryopreservation technique available that can effectively preserve both the ovarian tissue and its vascular supply required for reanastomosis. Antiapoptotic treatment with sphingosine-1-phosphate has also proven to be an effective approach in preventing chemotherapy-induced oocyte loss in mice [128]. Xenotransplantation of ovarian tissue to severe combined immunodeficient mice has been suggested when the risk of ovarian involvement with the primary tumor is high [129, 130]. However, aberrant microtubule organization and chromatin patterns, and the theoretical risk for infection with trans-species retroviruses, are among the significant concerns with this experimental procedure [131, 132]. In vitro growth of isolated follicles is another option; however, no success has been achieved in humans thus far [18, 133]. Recent animal studies showed that there may be germ stem cells in adult mice capable of replenishing ovarian reserve and that they may originate from the bone marrow, but the plausibility of this discovery in humans remains to be determined [134, 135].


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
 Conclusions
Disclosure of Potential...
 References
 Additional Reading
 
There are a number of options available to preserve fertility in breast cancer patients undergoing chemotherapy. The decisions of whether to resort to fertility preservation and which method to use depends on a number of factors, including the patient’s age, the type of adjuvant treatment, the time available before chemotherapy, and the length of delay to childbearing postchemotherapy (Fig. 1Go). The most recognized option for fertility preservation is embryo cryopreservation with either the partner’s or donor sperm. Oocyte cryopreservation is considered in single women who do not wish to use donor sperm. Both approaches require approximately 2 weeks of ovarian stimulation beginning with the onset of the patient’s menstrual cycle. Thus, it is crucial that these patients are referred to appropriate ART centers as soon as they are diagnosed with breast cancer. Recently developed ovarian stimulation protocols using tamoxifen and letrozole can be used to potentially increase the margin of safety in these patients. When and if a breast cancer patient does not have sufficient time to undergo ovarian stimulation, ovarian cryopreservation can be offered as the last resort. The benefit of ovarian protection by GnRHa treatment is unproven, and in the opinion of the authors, it should not be offered as a sole method of fertility preservation.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
 Conclusions
 Disclosure of Potential...
References
 Additional Reading
 
The authors indicate no potential conflicts of interest.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
 Conclusions
 Disclosure of Potential...
 References
Additional Reading
 

  1. Jemal A, Tiwari RC, Murray T et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8–29.[Abstract/Free Full Text]
  2. Hankey BF, Miller B, Curtis R et al. Trends in breast cancer in younger women in contrast to older women. J Natl Cancer Inst Monogr 1994;(16): 7–14.
  3. Higgins S, Haffty BG. Pregnancy and lactation after breast-conserving therapy for early stage breast cancer. Cancer 1994;73:2175–2180.[CrossRef][Medline]
  4. 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.[Abstract/Free Full Text]
  5. Ghafoor A, Jemal A, Ward E et al. Trends in breast cancer by race and ethnicity. CA Cancer J Clin 2003;53:342–355[Abstract/Free Full Text]
  6. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930–942.[CrossRef][Medline]
  7. Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001;344:1997–2008.[Free Full Text]
  8. Nystrom L, Rutqvist LE, Wall S et al. Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet 1993;341:973–978.[CrossRef][Medline]
  9. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451–1467.[CrossRef][Medline]
  10. Thewes B, Meiser B, Taylor 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.[Abstract/Free Full Text]
  11. Colleoni M, Rotmensz N, Robertson C et al. Very young women (<35 years) with operable breast cancer: features of disease at presentation. Ann Oncol 2002;13:273–279.[Abstract/Free Full Text]
  12. 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 2005;23:4347–4353.[Abstract/Free Full Text]
  13. Goodwin PJ, Ennis M, Pritchard KI et al. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999;17:2365–2370.[Abstract/Free Full Text]
  14. Avis NE, Crawford S, Manuel J. Psychosocial problems among younger women with breast cancer. Psychooncology 2004;13:295–308.[CrossRef][Medline]
  15. Partridge AH, Gelber S, Peppercorn J et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 2004;22:4174–4183.[Abstract/Free Full Text]
  16. Degner LF, Kristjanson LJ, Bowman D et al. Information needs and decisional preferences in women with breast cancer. JAMA 1997;277:1485–1492.[Abstract/Free Full Text]
  17. Lass A, Silye R, Abrams DC et al. Follicular density in ovarian biopsy of infertile women: a novel method to assess ovarian reserve. Hum Reprod 1997;12:1028–1031.[Abstract/Free Full Text]
  18. Oktay K, Nugent D, Newton H et al. Isolation and characterization of primordial follicles from fresh and cryopreserved human ovarian tissue. Fertil Steril 1997;67:481–486.[CrossRef][Medline]
  19. Warne GL, Fairley KF, Hobbs JB et al. Cyclophosphamide-induced ovarian failure. N Engl J Med 1973;289:1159–1162.[Medline]
  20. Ratts VS, Flaws JA, Kolp R et al. Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad. Endocrinology 1995;136:3665–3668.[Abstract]
  21. Tilly JL, Kolesnick RN. Realizing the promise of apoptosis-based therapies: separating the living from the clinically undead. Cell Death Differ 2003;10:493–495.[CrossRef][Medline]
  22. Bonadonna G, Valagussa P. Adjuvant systemic therapy for resectable breast cancer. J Clin Oncol 1985;3:259–275.[Medline]
  23. Sonmezer M, Oktay K. Fertility preservation in female patients. Hum Reprod Update 2004;10:251–266.[Abstract/Free Full Text]
  24. Meirow D, Lewis H, Nugent D et al. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool. Hum Reprod 1999;14:1903–1907.[Abstract/Free Full Text]
  25. Byrne J, Fears TR, Gail MH et al. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 1992;166:788–793.[Medline]
  26. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 2001;7:535–543.[Abstract/Free Full Text]
  27. Levine MN, Bramwell VH, Pritchard KI et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1998;16:2651–2658.[Abstract]
  28. Stone ER, Slack RS, Vovielli A, et al. Rate of chemotherapy related amenorrhea associated with adjuvant Adriamycin and Cytoxan and Adriamycin and Cytoxan followed by Taxol in early stage breast cancer. Breast Cancer Res Treat 2000;64:61a.
  29. Nabholtz J, Pienkowski T, Mackey J et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 2002;21:36a
  30. Brewer M, Gershenson DM, Herzog CE et al. Outcome and reproductive function after chemotherapy for ovarian dysgerminoma. J Clin Oncol 1999;17:2670–2675.[Abstract/Free Full Text]
  31. Tangir J, Zelterman D, Ma W et al. Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet Gynecol 2003;101:251–257.[CrossRef][Medline]
  32. Wallace WH, Shalet SM, Crowne EC et al. Gonadal dysfunction due to cis-platinum. Med Pediatr Oncol 1989:17:409–413.[Medline]
  33. Schmidt KL, Andersen CY, Loft A et al. Follow-up of ovarian function post-chemotherapy following ovarian cryopreservation and transplantation. Hum Reprod 2005;20:3539–3546.[Abstract/Free Full Text]
  34. Rivkees SA, Crawford JD. The relationship of gonadal activity and chemotherapy-induced gonadal damage. JAMA 1988;259:2123–2125.[Abstract/Free Full Text]
  35. Sanders JE, Buckner CD, Amos D et al. Ovarian function following marrow transplantation for aplastic anemia or leukemia. J Clin Oncol 1988;6:813–818.[Abstract/Free Full Text]
  36. Schilsky RL, Sherins RJ, Hubbard SM et al. Long-term follow up of ovarian function in women treated with MOPP chemotherapy for Hodgkin’s disease. Am J Med 1981;71:552–556[CrossRef][Medline]
  37. Teinturier C, Hartmann O, Valteau-Couanet D et al. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant 1998;22:989–994.[CrossRef][Medline]
  38. de Bruin JP, Dorland M, Spek ER et al. Age-related changes in the ultrastructure of the resting follicle pool in human ovaries. Biol Reprod 2004;70:419–424.[Abstract/Free Full Text]
  39. 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 2003;88:5307–5314.[Abstract/Free Full Text]
  40. 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 1995;64:991–994.[Medline]
  41. Scott RT, Toner JP, Muasher SJ et al. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651–654.[Medline]
  42. Del Mastro L, Venturini M, Sertoli MR et al. Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications. Breast Cancer Res Treat 1997;43:183–190.[CrossRef][Medline]
  43. Di Cosimo S, Alimonti A, Ferretti G et al. Incidence of chemotherapy-induced amenorrhea depending on the timing of treatment by menstrual cycle phase in women with early breast cancer. Ann Oncol 2004;15:1065–1071.[Abstract/Free Full Text]
  44. Bonadonna G, Moliterni A, Zambetti M et al. 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ 2005;330:217–222.[Abstract/Free Full Text]
  45. Valagussa P, Moliterni A, Zambetti M et al. Long-term sequelae from adjuvant chemotherapy. Recent Results Cancer Res 1993;127:247–255.[Medline]
  46. Emens LA, Davidson NE. Adjuvant hormonal therapy for premenopausal women with breast cancer. Clin Cancer Res 2003;9:486S–494S.[Abstract/Free Full Text]
  47. Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. The International Breast Cancer Study Group. Ann Oncol 1990;1:183–188.[Abstract/Free Full Text]
  48. Minton SE, Munster PN. Chemotherapy-induced amenorrhea and fertility in women undergoing adjuvant treatment for breast cancer. Cancer Control 2002;9:466–472.[Medline]
  49. Hortobagyi GN, Buzdar AU, Marcus CE et al. Immediate and long-term toxicity of adjuvant chemotherapy regimens containing doxorubicin in trials at M.D. Anderson Hospital and Tumor Institute. NCI Monogr 1986;(1):105–109.
  50. Oktay K, Libertella N, Oktem O et al. The impact of paclitaxel on menstrual function. Breast Cancer Res Treat 2005; 94 (Suppl 1):271s–272s.
  51. Friedlander M, Thewes B. Counting the costs of treatment: the reproductive and gynaecological consequences of adjuvant therapy in young women with breast cancer. Intern Med J 2003;33:372–379.[CrossRef][Medline]
  52. Thewes B, Meiser B, Duric VM et al. What survival benefits do premenopausal patients with early breast cancer need to make endocrine therapy worthwhile? Lancet Oncol 2005;6:581–588.[CrossRef][Medline]
  53. Castiglione-Gertsch M, O’Neill A, Price KN et al. Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2003;95:1833–1846.[Abstract/Free Full Text]
  54. Jakesz R, Hausmaninger H, Kubista E et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002;20:4621–4627.[Abstract/Free Full Text]
  55. Jonat W, Kaufmann M, Sauerbrei W et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002;20:4628–4635.[Abstract/Free Full Text]
  56. Eifel P, Axelson JA, Costa J et al. National Institute of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1–3 2000. J Natl Cancer Inst 2001;93:979–989.[Abstract/Free Full Text]
  57. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol 2001;19:3817–3827.[Free Full Text]
  58. Ataya K, Rao LV, Lawrence E et al. Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys. Biol Reprod 1995;52:365–372.[Abstract]
  59. Ataya K, Pydyn E, Ramahi-Ataya A et al. Is radiation-induced ovarian failure in rhesus monkeys preventable by luteinizing hormone-releasing hormone agonists?: preliminary observations. J Clin Endocrinol Metab 1995:8;790–795.
  60. Letterie GS. Anovulation in the prevention of cytotoxic-induced follicular attrition and ovarian failure. Hum Reprod 2004;19:831–837.[Abstract/Free Full Text]
  61. Blumenfeld Z, Avivi I, Linn S et al. Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum Reprod 1996;11:1620–1626.[Abstract/Free Full Text]
  62. Blumenfeld Z, Avivi I, Ritter M et al. Preservation of fertility and ovarian function and minimizing chemotherapy-induced gonadotoxicity in young women. J Soc Gynecol Investig 1999;6:229–239.[CrossRef][Medline]
  63. Recchia F, Sica G, De Filippis S et al. Goserelin as ovarian protection in the adjuvant treatment of premenopausal breast cancer: a phase II pilot study. Anticancer Drugs 2002;13:417–424.[CrossRef][Medline]
  64. Franke HR, Smit WM, Vermes I. Gonadal protection by a gonadotropin-releasing hormone agonist depot in young women with Hodgkin’s disease undergoing chemotherapy. Gynecol Endocrinol 2005;20:274–278[CrossRef][Medline]
  65. Waxman JH, Ahmed R, Smith D et al. Failure to preserve fertility in patients with Hodgkin’s disease. Cancer Chemother Pharmacol 1987;19:159–162.[Medline]
  66. Blumenfeld Z. Ovarian rescue/protection from chemotherapeutic agents. J Soc Gynecol Investig 2001;8(suppl 1):S60–S64.[CrossRef][Medline]
  67. Fox K, Scialla H, Moore H. Preventing chemotherapy-related amenorrhea using leuprolide during adjuvant chemotherapy for early stage breast cancer. Proc Am Soc Clin Oncol 2001;21:98a.
  68. Meirow D, Assad G, Dor J et al. The GnRH antagonist cetrorelix reduces cyclophosphamide-induced ovarian follicular destruction in mice. Hum Reprod 2004;19:1294–1299.[Abstract/Free Full Text]
  69. Danforth DR, Arbogast LK, Friedman CI. Acute depletion of murine primordial follicle reserve by gonadotropin-releasing hormone antagonists. Fertil Steril 2005;83:1333–1338.[CrossRef][Medline]
  70. Grigg AP, McLachlan R, Zaja J et al. Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant 2000;26:1089–1095.[CrossRef][Medline]
  71. Viviani S, Santoro A, Ragni G et al. Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 1985;21:601–605.[CrossRef][Medline]
  72. Key T, Appleby P, Barnes I et al. Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002;94:606–616.[Abstract/Free Full Text]
  73. Pike MC, Spicer DV, Dahmoush L et al. Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 1993;15:17–35.[Medline]
  74. Oktay K, Buyuk E, Davis O et al. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 2003;18:90–95.[Abstract/Free Full Text]
  75. Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo. Nature 1983;305:707–709.[CrossRef][Medline]
  76. Veeck LL, Bodine R, Clarke RN et al. High pregnancy rates can be achieved after freezing and thawing human blastocysts. Fertil Steril 2004;82:1418–1427.[CrossRef][Medline]
  77. Kosasa TS, McNamee PI, Morton C et al. Pregnancy rates after transfer of cryopreserved blastocysts cultured in a sequential media. Am J Obstet Gynecol 2005;192:2035–2039; discussion 2039–2040.[CrossRef][Medline]
  78. Omland AK, Fedorcsak P, Storeng R et al. Natural cycle IVF in unexplained, endometriosis-associated and tubal factor infertility. Hum Reprod 2001;16:2587–2592.[Abstract/Free Full Text]
  79. Ginsburg ES, Yanushpolsky EH, Jackson KV. In vitro fertilization for cancer patients and survivors. Fertil Steril 2001;75:705–710.[CrossRef][Medline]
  80. Dolmans MM, Demylle D, Martinez-Madrid B et al. Efficacy of in vitro fertilization after chemotherapy. Fertil Steril 2005;83:897–901.[CrossRef][Medline]
  81. Prest SJ, May FE, Westley BR. The estrogen-regulated protein, TFF1, stimulates migration of human breast cancer cells. FASEB J 2002;16:592–594.[Abstract/Free Full Text]
  82. Pittaway DE, Wentz AC. Evaluation of the exponential rise of serum estradiol concentrations in human menopausal gonadotropin-induced cycles. Fertil Steril 1983;40:763–767.[Medline]
  83. Pena JE, Chang PL, Chan LK et al. Supraphysiological estradiol levels do not affect oocyte and embryo quality in oocyte donation cycles. Hum Reprod 2002;17:83–87.[Abstract/Free Full Text]
  84. Chen SU, Lien YR, Tsai YY et al. Successful pregnancy occurred from slowly freezing human oocytes using the regime of 1.5 mol/l 1,2-propane-diol with 0.3 mol/l sucrose. Hum Reprod 2003;17:1412.
  85. Harper MJ, Walpole AL. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature 1966;212:87.[Medline]
  86. Harper MJ, Walpole AL. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil 1967;13:101–119.[Abstract/Free Full Text]
  87. Klopper A, Hall M. New synthetic agent for the induction of ovulation: preliminary trials in women. Br Med J 1971;1:152–154.[Abstract/Free Full Text]
  88. Prichard RS, Hill AD, Dijkstra B et al. The prevention of breast cancer. Br J Surg 2003;90:772–783.[Medline]
  89. Veronesi U, Maisonneuve P, Rotmensz N et al. Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst 2003;95:160–165.[Abstract/Free Full Text]
  90. Cox RI, Cox LW, Black TL. Test for ovarian function and responsiveness leading to ovulation induction. Lancet 1966;2:888–889.[Medline]
  91. Boostanfar R, Jain JK, Mishell DR Jr et al. A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction. Fertil Steril 2001;75:1024–1026.[CrossRef][Medline]
  92. Fisk NM, Templeton AA, Papadopoulos GC et al. Lack of effect of high-dose antioestrogen on the maturation and in-vitro fertilization of human oocytes. Hum Reprod 1989;4:584–587.[Abstract/Free Full Text]
  93. Isaacs RJ, Hunter W, Clark K. Tamoxifen as systemic treatment of advanced breast cancer during pregnancy--case report and literature review. Gynecol Oncol 2001;80:405–408.[CrossRef][Medline]
  94. Wu CH. Less miscarriage in pregnancy following Tamoxifen treatment of infertile patients with luteal phase dysfunction as compared to clomiphene treatment. Early Pregnancy 1997;3:301–305.[Medline]
  95. Klijn JG, Beex LV, Mauriac L et al. Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 2000;92:903–911.[Abstract/Free Full Text]
  96. Shushan A, Peretz T, Mor-Yosef S. Therapeutic approach to ovarian cysts in tamoxifen-treated women with breast cancer. Int J Gynaecol Obstet 1996;52:249–253.[CrossRef][Medline]
  97. Santen RJ. Recent progress in development of aromatase inhibitors. J Steroid Biochem Mol Biol 1990;37:1029–1035.[Medline]
  98. Pfister CU, Martoni A, Zamagni C et al. Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients. Biopharm Drug Dispos 2001;22:191–197.[CrossRef][Medline]
  99. Mouridsen H, Gershanovich M, Sun Y et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003;21:2101–2109.[Abstract/Free Full Text]
  100. Winer EP, Hudis C, Burstein HJ et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005;23:619–629.[Abstract/Free Full Text]
  101. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in post-menopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–1802[Abstract/Free Full Text]
  102. Duggan C, Marriott K, Edwards R et al. Inherited and acquired risk factors for venous thromboembolic disease among women taking tamoxifen to prevent breast cancer. J Clin Oncol 2003;21:3588–3593.[Abstract/Free Full Text]
  103. Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril 2002;77:776–780.[CrossRef][Medline]
  104. Mitwally MF, Casper RF. Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. J Soc Gynecol Investig 2004;11:406–415.[Medline]
  105. Oktay K. Further evidence on the safety and success of ovarian stimulation with letrozole and tamoxifen in breast cancer patients undergoing in vitro fertilization to cryopreserve their embryos for fertility preservation. J Clin Oncol 2005;23:3858–3859.[Free Full Text]
  106. Luthra R, Kirma N, Jones J et al. Use of letrozole as a chemopreventive agent in aromatase overexpressing transgenic mice. J Steroid Biochem Mol Biol 2003;86:461–467.[Medline]
  107. Hu Y, Cortvrindt R, Smitz J. Effects of aromatase inhibition on in vitro follicle and oocyte development analyzed by early preantral mouse follicle culture. Mol Reprod Dev 2002;61:549–559.[CrossRef][Medline]
  108. Oktay K, Cil A, Veeck L et al. Efficiency of IVF between frozen-thawed and fresh oocytes: a meta-analysis. Fertil Steril 2006 (in press).
  109. Gosden RG, Baird DT, Wade JC et al. Restoration of fertility to oophorectomized sheep by ovarian autografts stored at –196 degrees C. Hum Reprod 1994:9;597–603.[Abstract/Free Full Text]
  110. Liu J, Van der Elst J, Van den Broecke R et al. Live offspring by in vitro fertilization of oocytes from cryopreserved primordial mouse follicles after sequential in vivo transplantation and in vitro maturation. Biol Reprod 2001;64:171–178.[Abstract/Free Full Text]
  111. Salle B, Demirci B, Franck M et al. Long-term follow-up of cryopreserved hemi-ovary autografts in ewes: pregnancies, births, and histologic assessment. Fertil Steril 2003;80:172–177.[Medline]
  112. Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med 2000;342:1919.[Free Full Text]
  113. Radford JA, Lieberman BA, Brison DR et al. Orthotopic reimplantation of cryopreserved ovarian cortical strips after high-dose chemotherapy for Hodgkin’s lymphoma. Lancet 2001;357:1172–1175.[CrossRef][Medline]
  114. Oktay K, Economos K, Kan M et al. Endocrine function and oocyte retrieval after autologous transplantation of ovarian cortical strips to the forearm. JAMA 2001;286:1490–1493.[Abstract/Free Full Text]
  115. Callejo J, Salvador C, Miralles A et al. Long-term ovarian function evaluation after autografting by implantation with fresh and frozen-thawed human ovarian tissue. J Clin Endocrinol Metab 2001;86:4489–4494.[Abstract/Free Full Text]
  116. Oktay K, Buyuk E, Veeck L et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 2004; 363:837–840.[CrossRef][Medline]
  117. Donnez J, Dolmans MM, Demylle D et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;364:1405–1410.[CrossRef][Medline]
  118. Meirow D, Levron J, Eldar-Geva T et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med 2005;353:318–321.[Free Full Text]
  119. Curtin JP, Barakat RR, Hoskins WJ. Ovarian disease in women with breast cancer. Obstet Gynecol 1994;84:449–452.[Medline]
  120. Li CI, Anderson BO, Daling JR et al. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA 2003;289:1421–1424.[Abstract/Free Full Text]
  121. Morrow M. Breast. In: Greenfield LJ, Mulholland MW, Oldham KT et al., eds. Surgery: Scientific Principles and Practice, Third Edition. Philadelphia: Lippincott-Williams & Wilkins, Inc., 2001:1334–1372.
  122. Perrotin F, Marret H, Bouquin R et al. [Incidence, diagnosis and prognosis of ovarian metastasis in breast cancer.] Gynecol Obstet Fertil 2001;29:308–315. French.[CrossRef][Medline]
  123. Young RH, Scully RE. Metastatic tumors of the ovary. In: Kurman RJ, ed. Blaustein’s Pathology of the Female Genital Tract, Third Edition. New York: Springer Verlag, Inc., 1987:742–768.
  124. Sastre-Garau X, Jouve M, Asselain B et al. Infiltrating lobular carcinoma of the breast. Clinicopathologic analysis of 975 cases with reference to data on conservative therapy and metastatic patterns. Cancer 1996;77:113–120.[CrossRef][Medline]
  125. Liede A, Narod SA. Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2. Hum Mutat 2002;20:413–424.[CrossRef][Medline]
  126. Kauff ND, Satagopan JM, Robson ME et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346:1609–1615.[Abstract/Free Full Text]
  127. Arav A, Revel A, Nathan Y et al. Oocyte recovery, embryo development and ovarian function after cryopreservation and transplantation of whole sheep ovary. Hum Reprod 2005;20:3554–3559.[Abstract/Free Full Text]
  128. Morita Y, Perez GI, Paris F et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med 2000;6:1109–1114.[CrossRef][Medline]
  129. Oktay K, Newton H, Gosden RG. Transplantation of cryopreserved human ovarian tissue results in follicle growth initiation in SCID mice. Fertil Steril 2000;73:599–603.[CrossRef][Medline]
  130. Gook DA, McCully BA, Edgar DH et al. Development of antral follicles in human cryopreserved ovarian tissue following xenografting. Hum Reprod 2001;16:417–422.[Abstract/Free Full Text]
  131. Lucifero D, Mertineit C, Clarke HJ et al. Methylation dynamics of imprinted genes in mouse germ cells. Genomics 2002;79:530–538.[CrossRef][Medline]
  132. Kim SS, Kang HG, Kim NH et al. Assessment of the integrity of human oocytes retrieved from cryopreserved ovarian tissue after xenotransplantation. Hum Reprod 2005;20:2502–2508.[Abstract/Free Full Text]
  133. Revel A, Koler M, Simon A et al. Oocyte collection during cryopreservation of the ovarian cortex. Fertil Steril 2003:79:1237–1239.[CrossRef][Medline]
  134. Johnson J, Canning J, Kaneko T et al. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004;428:145–150.[CrossRef][Medline]
  135. Johnson J, Bagley J, Skaznik-Wikiel M et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005;122:303–315.[CrossRef][Medline]
  136. Cobleigh MA, Bines J, Harris D et al. Amenorrhea following adjuvant chemotherapy for breast cancer. Proc Am Soc Clin Oncol 1995;14:158a.
  137. Pagani O, O’Neill A, Castiglione M et al. Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI. Eur J Cancer 1998;34:632–640.[CrossRef][Medline]
  138. Vanhuyse M, Fournier C, Bonneterre J. Chemotherapy-induced amenorrhea: influence on disease-free survival and overall survival in receptor-positive premenopausal early breast cancer patients. Ann Oncol 2005;16:1283–1288.[Abstract/Free Full Text]
  139. Parulekar WR, Day AG, Ottaway JA et al. Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5. J Clin Oncol 2005;23:6002–6008.[Abstract/Free Full Text]
  140. Martin M, Pienkowski T, Mackey J et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:2302–2313.[Abstract/Free Full Text]

   ADDITIONAL READING
Top
 Learning Objectives
 Abstract
 Introduction
 The Impact of Chemotherapeutic...
 Assisted Reproduction Techniques...
 Cryopreservation of Ovarian...
 Future Directions
 Conclusions
 Disclosure of Potential...
 References
 Additional Reading
 



This article has been cited by other articles:


Home page
 Hum ReprodHome page
M. Sanchez-Serrano, E. Novella-Maestre, E. Rosello-Sastre, N. Camarasa, J. Teruel, and A. Pellicer
Malignant cells are not found in ovarian cortex from breast cancer patients undergoing ovarian cortex cryopreservation{dagger}
Hum. Reprod., September 1, 2009; 24(9): 2238 - 2243.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
M. Hickey, M. Peate, C.M. Saunders, and M. Friedlander
Breast cancer in young women and its impact on reproductive function
Hum. Reprod. Update, May 1, 2009; 15(3): 323 - 339.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
R. Beck-Fruchter, A. Weiss, and E. Shalev
GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data
Hum. Reprod. Update, November 1, 2008; 14(6): 553 - 561.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
I. Demeestere, P. Simon, S. Emiliani, A. Delbaere, and Y. Englert
Fertility Preservation: Successful Transplantation of Cryopreserved Ovarian Tissue in a Young Patient Previously Treated for Hodgkin's Disease
Oncologist, December 1, 2007; 12(12): 1437 - 1442.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
Z. Blumenfeld
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, September 1, 2007; 12(9): 1044 - 1054.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
K. Oktay, M. Sonmezer, O. Oktem, K. Fox, G. Emons, and H. Bang
Absence of Conclusive Evidence for the Safety and Efficacy of Gonadotropin-Releasing Hormone Analogue Treatment in Protecting Against Chemotherapy-Induced Gonadal Injury
Oncologist, September 1, 2007; 12(9): 1055 - 1066.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sonmezer, M.
Right arrow Articles by Oktay, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sonmezer, M.
Right arrow Articles by Oktay, K.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS