Abstract
Fertility preservation (FP) has become a specialized branch of reproductive medicine aimed at preserving the potential for future genetic parenthood for young adults, or even children, at risk of sterility before undergoing cancer treatment. Thanks to more refined chemotherapy and radiotherapy protocols, the five-year survival rates for many cancers have steadily increased; e.g., survivorship for Hodgkin’s lymphoma went from 86% to 98% and for breast cancer from 78% to 91% in the last 25 years.
Introduction
Fertility preservation (FP) has become a specialized branch of reproductive medicine aimed at preserving the potential for future genetic parenthood for young adults, or even children, at risk of sterility before undergoing cancer treatment. Thanks to more refined chemotherapy and radiotherapy protocols, the five-year survival rates for many cancers have steadily increased; e.g., survivorship for Hodgkin’s lymphoma went from 86% to 98% and for breast cancer from 78% to 91% in the last 25 years[1,2]. However, the risk of sterilization or early menopause by the effects of ionizing radiation or alkylating agents such as cyclophosphamide, procarbazine, and platinum-based drugs is high and therefore preserving future fertility is of paramount importance for the future quality of life-adjusted years[3,4].
Lately, the indications for FP have expanded and today an increasing number of healthy, mostly single and unpartnered, women are also resorting to FP, namely elective oocyte cryopreservation, to safeguard their wishes of future reproduction while postponing motherhood[5,6]. All the options available for FP are considered established and standard of care, except ovarian tissue cryopreservation and re-transplantation that is still considered experimental (although the ASRM at the time of writing is evaluating whether to remove the label of experimental). In this chapter we describe the various options available to preserve fertility in women for medical and nonmedical indications and will elucidate the ideal, patient-centered approach for medical and elective oocyte cryopreservation as revealed by some recent studies[7,8].
Medical Indications and Options for FP
International guidelines on FP in patients with cancer strongly suggest that all patients of reproductive age at risk of iatrogenic infertility should be referred to reproductive specialists prior to starting potentially gonadotoxic treatments, so as to be fully informed about FP options[4,9]. Ovarian dysfunction after chemotherapy has been well described. The nature and extent of this damage depends on the type of the chemotherapy drug given, the dose received, the underlying health conditions, and the age of the patient at the time of treatment. For example, cytotoxic agents (cyclophosphamide and procarbazine) are considered particularly gonadotoxic, able to deplete the primordial ovarian follicular pool and thus at high risk for causing premature ovarian insufficiency (POI). Women receiving preconditioning and radiotherapy for bone marrow transplantation are also at a high risk for future infertility[4,9]. Although Wallace and colleagues[10] developed an age-predictive model for ovarian failure after treatment with a known dose of radiotherapy, because of the varied and individual nature of the gonadal insult after radiotherapy, it is often extremely difficult to give a young patient an accurate assessment of the risk to fertility and the likelihood of POI after cancer treatment. Given the inability to predict future fertility, whenever possible, it is always better to offer potential benefits of cryopreservation.
An increasing number of patients diagnosed with non-oncological conditions are also being referred to specialists for discussing FP[4]. These are patients with autoimmune diseases (systemic lupus erythematosus, Behcet’s disease, granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), and so on), or requiring hematopoietic stem cell transplantation (autologous or allogeneic) (sickle cell anemia, thalassemia major, aplastic anemia), or at risk of POI for known genetic causes (e.g., mosaic Turner syndrome, galactosemia), or transgender.
A number of options are available for FP and the most commonly offered are: (a) oocyte freezing, (b) embryo freezing, (c) ovarian transposition, (d) suppression of folliculogenesis, and (e) ovarian tissue cryopreservation. Some of these options are compared in Table 10.1.
Table 10.1 Comparison of methods of FP
| Oocyte cryopreservation | Embryo cryopreservation | Ovarian tissue cryopreservation | Suppression of folliculogenesis | |
|---|---|---|---|---|
| Requires ovarian stimulation | Yes | Yes | No | No |
| Need partner or donor sperm | No | Yes | No | No |
| Treatment delay (two weeks) | Yes | Yes | No | No |
| Requires surgery | No | No | Yes | No |
| Applicable in prepubertal girls | No | No | Yes | No |
| Return endocrine function | No | No | Yes | Yes/no |
| Live births | Yes | Yes | Yes | Yes |
| Experimental | No | No | Yes | Unclear |
Oocyte and embryo cryopreservation via IVF are the most widely established and available treatment options for both preservation and postponement of fertility[4,9]. In general, the IVF procedure requires, at the most, two weeks of delaying treatment and involves stimulation of the patient’s ovaries with specific protocols, which can be started at any point in the menstrual cycle (random starts). For patients with diagnosis of breast cancer, letrozole (an aromatase inhibitor) is part of the protocol to keep the levels of E2 low. Oocyte retrieval is carried out via ultrasound-guided transvaginal aspiration and metaphase II oocytes are either cryopreserved by vitrification or, in the event of embryo freezing, they are fertilized, and the resulting embryos cryopreserved on day one as two pronuclei, or about five days later at the blastocyst stage of development. When the patient is cancer free and cleared to attempt pregnancy, in the event of POI, she can use the oocytes or the cryopreserved embryos for a chance at motherhood.
Transposition of the ovaries (oophoropexy) outside of the pelvis is indicated in patients who require pelvic radiation. This conservative surgical option may be preferred in either prepubertal patients or patients who hope to maintain long-term endocrine function. The procedure is performed by laparoscopy[11] and has been successful in 16–90% of the reported cases, with the variation likely a result of the inability to prevent scatter radiation, differing doses of radiation used, and the use of combination chemotherapy. It is important to note that oophoropexy must be performed close to the time of radiotherapy as the ovaries may migrate over extended periods back into the pelvis. Also, patients should be aware that once cured from their cancer, due to the new location of the ovaries away from the fallopian tubes, to achieve a pregnancy they may require IVF.
Suppression of folliculogenesis with GnRHa for FP is still controversial with conflicting results about the efficacy in protecting from the risk of POI to the point that the American Society of Clinical Oncology[12] still suggest oocyte or embryo freezing if the cancer treatment can be delayed for two weeks (Table 10.1 provides a comparison of methods for FP).
When the time interval between cancer diagnosis and initiation of treatment is sufficient and patients choose to undergo COS for oocyte retrieval (medical egg freezing), they should be counseled that, in general, conventional COS can provide an average of 8.5±6.4 metaphase II (MII) oocytes for vitrification per cycle, depending on the woman’s age and ovarian reservation[13]. However, patients should also be made aware that, so far, only very few women with cancer have returned to use their cryopreserved oocytes; therefore, the future success rate quoted is mainly based on data from egg donation cases and from nonmedical cases of oocyte cryopreservation. Extrapolating from these cases, it is suggested that around 20 vitrified oocytes are required to achieve a live birth[14,15].
Ovarian tissue cryopreservation (OTC) is the only possible option if the chemotherapy or radiotherapy must start immediately, with no time for ovarian stimulation. Although the life span of re-transplanted ovarian tissue varies, reports of continuation of function of re-transplanted frozen/thawed ovarian cortical strip for more than 5–10 years, and close to 100 healthy live births, have been documented[16].
OTC has not been reserved solely for women with malignant disease. Hematopoietic stem cell transplantation (HSCT) has been increasingly used in recent decades for noncancerous disease such as benign hematological disease (sickle cell anemia, thalassemia major, and aplastic anemia) and autoimmune disease previously unresponsive to immunosuppressive therapy (systemic lupus erythematosus, Behcet’s disease, granulomatosis with polyangiitis, and autoimmune thrombocytopenia)[17]. A large retrospective survey of pregnancy outcomes after HSCT involving 37 362 patients revealed that only 0.6% of patients conceived after autologous or allogenic HSCT. Other benign diseases have high risk of POI such as recurrent large ovarian endometriomas or recurrent ovarian mucinous cysts, and mosaic Turner syndromes[18].
For prepubertal girls, isolation and cryopreservation of ovarian cortical strips/primordial follicles followed by future re-transplant or in vitro maturation of gametes when fertility is desired is a possible option. However, much more research is required to refine these modalities prior to expanding the offerings to very young patients as proven therapies[19].
Patient-centered Approach for Elective and Medical Oocyte Cryopreservation
Elective Egg Freezing
Around the globe, the demand for elective egg freezing (EEF) is growing. For example, in the United States between 2013 and 2018, the total number of egg freezing cycles for all forms of FP jumped from 5000 to 12 000, according to the most recent Society for Assisted Reproductive Technology statistics[6,8,20,21].
Oocyte cryopreservation, thanks to the successful introduction of the vitrification technique, has also gained increasing acceptance for healthy women who are hoping to preserve their reproductive potential[20,22,23]. Oocyte cryopreservation in healthy women has been called “social egg freezing,” “nonmedical egg freezing,” “elective oocyte cryopreservation,” “elective FP,” and “oocyte banking for anticipated gamete exhaustion.” Given the ongoing lack of agreement on the best nomenclature, we suggested “EEF” be added to the glossary of accepted terms[6] because it may most closely mirror women’s preferred usage. In a large-scale interview-based study among 150 women who had completed EEF through four American IVF clinics and three in Israel, the chapter authors and colleagues reported that the majority (85%) of women in the study were unpartnered, while 15% had partners at the time of EEF[6]. Six pathways to EEF were found among women without partners (being single, divorced, broken up, deployed overseas, single mother, or career planner), with career planning being the least common reason for EEF. Among women with partners, four pathways to EEF were found (relationship too new or uncertain, partner not ready to have children, partner refusing to have children, or partner having multiple partners). Therefore, partnership problems, not career planning, lead most women on pathways to EEF. These pathways should be recognized in fertility clinics when offering consultations and advice to women planning EEF[6,20].
Several other anonymous surveys have also provided evidence regarding age and reasons for women’s EEF motivations. A survey of 183 women who had completed at least one cycle of EEF during the years 2005–2011 showed that 84% were age 35 or older, and 88% had completed at least one cycle of EEF because they lacked a partner[24]. Another survey of 86 women in Belgium found that women were 36.7 years of age on average, and the overwhelming majority, 81%, lacked partners[25]. Similarly, in Australia, a survey of 96 women described as “socioeconomically advantaged” – highly educated (89%), professionals (88%), who owned private health insurance (93%) – had completed EEF between 1999 and 2014. Of these, 48% were 38 years or older, 90% were unpartnered, and 94% had not returned to use their eggs because they were not interested in being single mothers[26].
Our recently published qualitative assessments of 150 women’s (114 in the United States and 36 in Israel) specific life circumstances and pathways to EEF confirmed that highly educated professional women are postponing motherhood and resorting to EEF for lack of a suitable partner rather than for career planning[6,8]. The average age for EEF was 36, with about three-quarters of women in both countries pursuing EEF in their late thirties. Almost all women who froze their eggs in both countries were highly educated and were ethnically and racially diverse. Most women (85%) were without partners at the time of EEF. However, being “partnered” or “unpartnered” are not monolithic categories, especially in terms of motivation to pursue EEF. Women in both categories faced a variety of different life circumstances that led them on the path to EEF[8]. Most women lamented the shortage of eligible men, especially men of equal educational and professional backgrounds. In some cases, women had tried “dating down” to widen their partnership possibilities, but they reported that less educated or less successful men had often acted as though they were “intimidated.” Without a partner, these highly educated professional women had turned to EEF, usually in their late thirties, to “buy time,” while continuing to search for a partner with the hope of future marriage and motherhood.
Among the women without partners, 17% had been previously married and 12% were never married but had recently “broken up” from long-term relationships. Ex-husbands were variously described by women as being unfaithful, over-controlling, narcissistic, alcoholic, or asexual. In the breakups group the reasons were their partners did not want children or changed their minds about having children, or already had children and did not want more, or were significantly younger and not ready to have children[20].
Only six women had undertaken EEF on the eventual path to single motherhood. Five of these women froze their eggs first, then decided to become “single mothers by choice.”
Most considered single motherhood a very difficult choice: a “last resort” or “plan B.” Women often cited the high financial costs of raising a child alone, especially in expensive cities such as New York, San Francisco, or Tel Aviv. For others, single motherhood suggested “desperation” or “failure,” and they rejected it out of hand. Whether this EEF-assisted pathway to single motherhood will continue to grow is uncertain, but in this study, it comprised a small category among unpartnered women with the financial means to raise a child on their own.
Only one woman described her path to EEF as a career strategy. At age 30, she was significantly younger than most women in the study and was clear in her interview that her decision to freeze her eggs had allowed her to focus on her new career.
Fifteen percent of the women in the study were partnered at the time of EEF. About half of these partnered women were in secure, stable relationships with men who wanted to have children. But, in most cases, male partners were not yet “ready” to become fathers, usually because they were completing their education, making significant career moves, or were significantly younger (e.g., 5–18 years) than their female partners. Among partnered women, deployment overseas (8%), either in the military or for humanitarian organizations, was another reason for resorting to EEF. These long-term deployments sometimes last up to three years. These women’s postings were also often in difficult and dangerous locations, including war zones and refugee camps.
Even though this “men as partners” problem has been well defined in public health scholarship, rarely has it been articulated in the assisted reproduction literature, so it is important to recognize the magnitude and heterogeneity of partnership problems in these women’s lives. In both the United States and Israel, highly educated, professional women were experiencing their reproductive lives as being in jeopardy. EEF was their “technological concession”: a way of putting their reproduction “on hold” in the absence of stable relationships with men committed to marriage and family making. For women themselves, this “men as partners” problem and the resultant “need” for EEF may be experienced as difficult, frustrating, and emotionally wrenching.
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