Advances in cancer care have improved survival, driving the need to mitigate the side effects of cancer therapy to improve the quality of life of cancer survivors. Use of fertility preservation has grown given the potential gonadotoxicity of chemotherapy and radiation, the increasing rate of treatment success, and the strong desire for childbearing in cancer survivors. Current options include embryo and oocyte cryopreservation, ovarian tissue cryopreservation, gonadal suppression, and ovarian transposition. Consultation with a reproductive endocrinology and infertility specialist trained in fertility preservation provides cancer patients an individualized risk assessment for future gonadal failure and discussion of potential fertility preservation options.
The 2007 Surveillance, Epidemiology, and End Results program estimates that there are 11.7 million cancer survivors in the United States, comprising 3.9% of the US population. Of these survivors, 54% are female, and 4.5% of all cancer survivors are <40 years of age, resulting in >275,000 female cancer survivors of reproductive age. The most common cancers in premenopausal women are breast, thyroid, melanoma, cervical, and uterine cancer and Hodgkin lymphoma. Fortunately oncologic care of these conditions continues to improve resulting in increased survival. With this increase in survival comes a new challenge–a need to decrease the morbidity of cancer treatment and improve the quality of life of the survivors.
Chief among the concerns of young cancer patients is that their disease or the treatment of their disease will affect future fertility. Surveys of young women with breast cancer have shown that the majority are concerned about the effect of treatment on their fertility, and that for some, infertility concerns influenced treatment decisions. For this reason the American Society of Clinical Oncology (ASCO) released recommendations in 2006 detailing the need to address fertility when treating reproductive-aged cancer patients. These recommendations include assessing the potential gonadotoxicity of treatment and providing access to fertility preservation providers.
The utilization of fertility preservation has grown since the 2006 ASCO guidelines. While sperm and embryo banking remain standard treatments, additional options for women include oocyte banking, ovarian tissue cryopreservation, and ovarian transposition. To conduct this review a comprehensive search was conducted in PubMed using the search terms “fertility preservation,” “oncofertility,” “embryo cryopreservation,” “oocyte cryopreservation,” “ovarian tissue cryopreservation,” “gonadal suppression,” and “cancer.” The bibliography of each article was reviewed to identify any additional articles of interest. The following is a summary of the current options for fertility preservation in women with cancer, highlighting the current knowledge regarding the safety and success of each option ( Table 1 ).
| Technique | Advantages | Disadvantages |
|---|---|---|
| Embryo banking |
|
|
| Oocyte banking |
|
|
| In vitro maturation of oocytes |
|
|
| Ovarian tissue cryopreservation |
|
|
| Gonadal suppression with GnRH agonists |
|
|
| Ovarian transposition |
|
|
Effect of chemotherapy and radiation on fertility
Female fertility requires normal functioning of the ovaries, fallopian tubes, and uterus. While the surgically managed gynecologic cancers pose an obvious threat to future fertility by removal of these organs, the majority of cancer treatments impair future fertility by decreasing ovarian reserve. Oogenesis occurs in utero and women are born with a finite number of oocytes; this pool of oocytes is gradually depleted leading to the cessation of menses and menopause. Chemotherapy and radiation affect fertility by accelerating this depletion of the ovarian follicle pool.
The degree to which chemotherapy affects ovarian reserve depends on a number of factors, including the age of the patient, chemotherapy agent used, and duration of treatment. Alkylating agents, such as cyclophosphamide and ifosfamide, carry the greatest risk for ovarian failure. Antimetabolites affect only dividing cells and pose less risk. With regard to age, the younger the age of exposure, the less risk of ovarian failure; one prospective study of women with breast cancer treated with multiagent chemotherapy found an incidence of amenorrhea (12 months without menses) of 10% in women <35 years, 50% for women between 35-40 years, and 75% for women >40 years of age. Importantly, menstrual cyclicity does not necessarily indicate fertility; a recent survey reported that infertility in cancer survivors who resume cycling is likely underestimated. The survey results revealed that the prevalence of infertility in survivors of breast cancer and lymphoma was 15-30% in women diagnosed at age 25 years and 25-50% in women diagnosed at age 35 years.
Total body, craniospinal, abdominal, and pelvic radiation can harm the ovary, and the extent of damage depends on both the total radiation exposure and age at the time of treatment. Current radiotherapy planning can both attempt to minimize gonadal exposure as well as calculate the dose to the ovaries. Using the calculated dose to the ovaries, the risk of ovarian failure and age of anticipated ovarian failure can be estimated; 16 Gy has been shown to be a sterilizing dose at age 20 years, and 10 Gy at age 45 years. Exposure to the uterus must be considered as well; exposure of the prepubertal uterus to doses between 14-30 Gy are likely to result in poor uterine growth and uterine dysfunction. Brain irradiation involving the pituitary can result in hypopituitarism and secondary gonadal failure. In this case, ovarian function and fertility can be recovered by use of gonadotropin therapy.
Embryo banking
The most established and reliable method of fertility preservation for women is embryo banking. The protocol for embryo banking is similar to an in vitro fertilization (IVF) cycle done for patients with infertility with the exception of the embryo transfer. The female patient undergoes controlled ovarian stimulation (COS) using gonadotropin injections to promote multifollicular growth. Dosing of the protocol is determined by assessing ovarian reserve using the same methods used for female infertility patients: basal serum follicle-stimulating hormone level, antral follicle count, and/or serum antimüllerian hormone level. Data have been mixed on whether cancer patients have a reduced response to gonadotropin stimulation compared to age-matched controls; overall it appears that with the same amount of drug they obtain slightly fewer but still an adequate number of oocytes (11.7 vs 13.5, P = .002). Following COS an oocyte retrieval procedure is performed, typically under conscious sedation using transvaginal ultrasound-guided needle aspiration. The oocytes are then fertilized in the laboratory and the embryos created are frozen for future use. IVF has been performed for over 30 years and embryo cryopreservation is a standard assisted reproduction technique. Thus, embryo banking is a fertility preservation option with a proven track record and established success rates.
Modifications to standard COS are often made to adapt this treatment to best suit the cancer patient. For example, COS is typically started in the early follicular phase or after hypothalamic-pituitary-ovary axis down-regulation with a gonadotropin-releasing hormone (GnRH) agonist. When a patient is diagnosed with cancer there is often urgency from both the patient and oncology provider to start chemotherapy. If the patient is in the early follicular phase of her menstrual cycle, ovarian stimulation can begin immediately using a GnRH antagonist protocol; in this case, stimulation and oocyte retrieval can be accomplished in 10-14 days. However, if the patient is late follicular, periovulatory, or luteal phase, standard IVF protocols would require waiting up to 3 weeks for a menstrual cycle to start. As this may be an unacceptable delay, alternative protocols to initiate COS in the luteal phase have been researched. Use of a high-dose GnRH antagonist to hasten the luteal phase as well as simply starting ovarian stimulation in the luteal phase have both been shown to have satisfactory results. Studies have been reassuring that the start of chemotherapy is not significantly delayed in women who choose to undergo ovarian stimulation for fertility preservation, and early referral to a fertility preservation provider (eg, prior to breast surgery) can shorten this time and provide the opportunity for >1 banking cycle.
Another modification of standard COS may be appropriate for patients with estrogen-sensitive tumors, such as estrogen receptor–positive breast cancers. During COS, circulating serum estradiol levels can be 10- to 15-fold higher than physiologic estradiol levels. While it is uncertain if this brief supraphysiologic estrogen exposure affects tumor growth, many providers have introduced the use of an aromatase inhibitor during COS to lower the serum estrogen levels and minimize estrogen exposure. Letrozole has been shown to decrease estrogen exposure without compromising oocyte yield or fertilization rate when used in breast cancer patients undergoing IVF prior to chemotherapy. A prospective cohort of breast cancer patients referred for fertility preservation demonstrated that those who underwent COS using letrozole and gonadotropins for oocyte or embryo banking had a recurrence rate and survival that was similar on short-term (2- to 3-year) follow-up to those who elected not to undergo COS/IVF. While this evidence is limited, it provides some reassurance that COS is not significantly compromising cancer treatment outcomes. Studies that demonstrate a benefit of the use of aromatase inhibitors during COS are currently lacking. Given the theoretical benefit of minimizing estrogen exposure and data that IVF outcomes are not compromised, it is reasonable to consider this adjunct therapy in patients with estrogen-sensitive tumors undergoing COS.
Embryo banking
The most established and reliable method of fertility preservation for women is embryo banking. The protocol for embryo banking is similar to an in vitro fertilization (IVF) cycle done for patients with infertility with the exception of the embryo transfer. The female patient undergoes controlled ovarian stimulation (COS) using gonadotropin injections to promote multifollicular growth. Dosing of the protocol is determined by assessing ovarian reserve using the same methods used for female infertility patients: basal serum follicle-stimulating hormone level, antral follicle count, and/or serum antimüllerian hormone level. Data have been mixed on whether cancer patients have a reduced response to gonadotropin stimulation compared to age-matched controls; overall it appears that with the same amount of drug they obtain slightly fewer but still an adequate number of oocytes (11.7 vs 13.5, P = .002). Following COS an oocyte retrieval procedure is performed, typically under conscious sedation using transvaginal ultrasound-guided needle aspiration. The oocytes are then fertilized in the laboratory and the embryos created are frozen for future use. IVF has been performed for over 30 years and embryo cryopreservation is a standard assisted reproduction technique. Thus, embryo banking is a fertility preservation option with a proven track record and established success rates.
Modifications to standard COS are often made to adapt this treatment to best suit the cancer patient. For example, COS is typically started in the early follicular phase or after hypothalamic-pituitary-ovary axis down-regulation with a gonadotropin-releasing hormone (GnRH) agonist. When a patient is diagnosed with cancer there is often urgency from both the patient and oncology provider to start chemotherapy. If the patient is in the early follicular phase of her menstrual cycle, ovarian stimulation can begin immediately using a GnRH antagonist protocol; in this case, stimulation and oocyte retrieval can be accomplished in 10-14 days. However, if the patient is late follicular, periovulatory, or luteal phase, standard IVF protocols would require waiting up to 3 weeks for a menstrual cycle to start. As this may be an unacceptable delay, alternative protocols to initiate COS in the luteal phase have been researched. Use of a high-dose GnRH antagonist to hasten the luteal phase as well as simply starting ovarian stimulation in the luteal phase have both been shown to have satisfactory results. Studies have been reassuring that the start of chemotherapy is not significantly delayed in women who choose to undergo ovarian stimulation for fertility preservation, and early referral to a fertility preservation provider (eg, prior to breast surgery) can shorten this time and provide the opportunity for >1 banking cycle.
Another modification of standard COS may be appropriate for patients with estrogen-sensitive tumors, such as estrogen receptor–positive breast cancers. During COS, circulating serum estradiol levels can be 10- to 15-fold higher than physiologic estradiol levels. While it is uncertain if this brief supraphysiologic estrogen exposure affects tumor growth, many providers have introduced the use of an aromatase inhibitor during COS to lower the serum estrogen levels and minimize estrogen exposure. Letrozole has been shown to decrease estrogen exposure without compromising oocyte yield or fertilization rate when used in breast cancer patients undergoing IVF prior to chemotherapy. A prospective cohort of breast cancer patients referred for fertility preservation demonstrated that those who underwent COS using letrozole and gonadotropins for oocyte or embryo banking had a recurrence rate and survival that was similar on short-term (2- to 3-year) follow-up to those who elected not to undergo COS/IVF. While this evidence is limited, it provides some reassurance that COS is not significantly compromising cancer treatment outcomes. Studies that demonstrate a benefit of the use of aromatase inhibitors during COS are currently lacking. Given the theoretical benefit of minimizing estrogen exposure and data that IVF outcomes are not compromised, it is reasonable to consider this adjunct therapy in patients with estrogen-sensitive tumors undergoing COS.
Oocyte banking
While there are many years of experience with embryo banking, this option may not be acceptable to all women. Female cancer patients who do not have a male partner may elect to fertilize their oocytes with donor sperm to bank embryos, however this limits their reproductive options and may introduce ethical dilemmas with future use. Oocyte cryopreservation is an option for fertility preservation for young or adolescent females, unpartnered women, women who are partnered but wish to maintain maximum reproductive flexibility, and those patients who have an ethical or religious concern regarding embryo disposition.
Oocyte cryopreservation has advanced greatly over the past 5-6 years. Initial attempts to freeze oocytes were unsuccessful; the delicate spindle structure in the metaphase II oocyte and its water content make the cell particularly sensitive to damage by ice crystals during freezing and thawing. Furthermore, oocyte cryopreservation results in hardening of the zona pellucida, which hampers fertilization. This obstacle can now be overcome by using intracytoplasmic sperm injection (ICSI). An initial metaanalysis of the efficiency of IVF-ICSI with oocytes frozen using the slow freeze method compared to nonfrozen oocytes showed the frozen oocytes had significantly lower rates of fertilization (65% vs 77%), implantation (15% vs 40%), and live birth per embryo transfer (32% vs 60%).
The slow freeze method of cryopreservation involves the use of a cryoprotectant that permeates and dehydrates the cell as it is slowly cooled, which minimizes the formation of intracellular ice crystals. A newer method of cryopreservation, vitrification, uses a highly concentrated cryoprotectant and ultrarapid freezing that more effectively avoids ice crystal formation. Studies that compare the 2 methods demonstrate that spindle and chromosomal disruption occur after both methods but are less common following vitrification. Findings from the metaanalysis on oocyte cryopreservation showed that vitrification had more promising results. Rates of fertilization (75%), implantation (21%), and live birth per transfer (39%) were closer to those seen with nonfrozen oocytes. Additional experience and advances in cryopreservation have continued to close the gap, and some centers report IVF outcomes with cryopreserved oocytes that are comparable to fresh IVF/ICSI rates ( Table 2 ). Of note, the majority of studies on oocyte cryopreservation have been performed using oocytes from healthy donors or good prognosis patients. It is uncertain if female cancer patients would have similar outcomes; this remains to be explored.
| Reference | Method | Oocyte thaw survival | Fertilization rate | Implantation rate | Clinical pregnancies per transfer | Live births per transfer | Live births per thawed oocyte |
|---|---|---|---|---|---|---|---|
| Oktay et al, 2006 (metaanalysis, 41 reports included 1997 through 2006) | Slow freeze | Data not available | 309/476 (65%) a | 34/222 (15%) a | 28/74 (38%) a | 24/74 (32%) a | 76/4000 (2%) b |
| Vitrification | 481/638 (75%) c | 69/336 (21%) c | 51/100 (51%) c | 39/100 (39%) c | 39/851 (5%) c | ||
| Control | 2788/3637 (77%) | 436/1095 (40%) | 272/397 (69%) | 240/397 (60%) | Not applicable | ||
| Grifo and Noyes, 2010 (single-center series, 22 subjects) | Slow freeze | 140/159 (88%) | 118/140 (84%) | 22/53 (42%) | 14/23 (61%) | 13/23 (57%) d | 13/322 (4%) |
| Vitrification | 155/163 (95%) | 115/155 (75%) | |||||
| Rienzi et al, 2012 (multicentered series, 450 subjects) | Vitrification | 2304/2721 (85%) | 1642/2182 (75%) | Data not available | 166/423 (39%) | 128/436 (29%) | 128/2721 (5%) |
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