F e r t i l i t y Pres e r v a t i o n i n the Age of Assisted R e p ro d u c t i v e Tec h n o l o g i e s Paul R. Brezina, MD, MBAa,b,c,*, William H. Kutteh, Amelia P. Bailey, MDc, Jianchi Ding, PhDd, Raymond W. Ke, MDa,b,c, James L. Klosky, PhDe

MD, PhD

a,b,c

,

KEYWORDS  Fertility preservation  Cryopreservation  Freezing  Egg  Sperm  Oocyte  Cancer  Oncology KEY POINTS  Strategies used to accomplish fertility preservation are many.  Over the past several decades, new technologies, especially related to assisted reproductive technologies and in vitro fertilization, have greatly expanded ways to accomplish fertility preservation. These advances have also grown the indications for pursing fertility potential in general.  Surely, advances in technology will continue to be optimized in the future.  By all indicators, the role for fertility preservation in society and medicine is likely to only increase over the next several decades.

The authors have no pertinent disclosures and conflicts of interest. Sources of Funding: None. Contributors: P.R. Brezina, A.P. Bailey, R.W. Ke, J.L. Klosky, and W.H. Kutteh primarily searched the literature and wrote the first draft of the article; P.R. Brezina is guarantor. Competing Interests: All authors have completed the Unified Competing Interest form and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. a Vanderbilt University School of Medicine, 1161 21st Avenue South, R-1200 Medical Center North, Nashville, TN 37232-2521, USA; b Department of Surgery, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA; c Fertility Associates of Memphis, 80 Humphreys Center, Suite 307, Memphis, TN 38120-2363, USA; d IVF Laboratory, Fertility Associates of Memphis, 80 Humphreys Center, Suite 307, Memphis, TN 38120, USA; e Cancer Survivorship, St. Jude Children’s Research Hospital, 262 Danny Thomas Place–MS 740, Memphis, TN 38105-3678, USA * Corresponding author. Vanderbilt University School of Medicine, 1161 21st Avenue South, R-1200 Medical Center North, Nashville, TN 37232-2521. E-mail address: [email protected] Obstet Gynecol Clin N Am 42 (2015) 39–54 http://dx.doi.org/10.1016/j.ogc.2014.09.004 obgyn.theclinics.com 0889-8545/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

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INTRODUCTION

Reproduction has been and will always be central to the human experience. Many individuals experience situations that may compromise their future fertility. The reasons for this are many, ranging from social pressure to defer childbearing, to exposure to gonadotoxic agents (eg, chemotherapy) that damage reproductive organs. Both men and women may be placed in environments that could compromise their future fertility. Historically, the options for preserving fertility were quite limited. Women could choose to have children earlier in life than they would have ideally chosen at the possible expense of their careers. Men known to have a malignancy could undergo cryopreservation (freezing) of their sperm before being exposed to caustic chemotherapy. Barring these 2 approaches, the options for fertility preservation, particularly for women, have been quite limited. The past several decades, however, have seen technologies that have changed the historical limitations regarding fertility preservation. Assisted reproductive technologies (ART) associated specifically with in vitro fertilization (IVF) have ushered in new tools that are now routinely used to preserve fertility. Cryopreservation of unfertilized eggs and embryos gives a new set of options for women desiring fertility preservation for a variety of indications. An outline of available technologies currently used for fertility preservation is shown in Box 1. In addition, the use of surgical, medical, pharmacologic, and psychological interventions offer mechanisms to facilitate fertility preservation, particularly in the setting of oncology. This review attempts to offer an overview of the state of the art within fertility preservation. CRYOPRESERVATION TECHNOLOGIES AVAILABLE Sperm Cryopreservation

The ability to cryopreserve human sperm was first established in 1953 in a report by Bunge and Sherman.1 Since this time, the use of sperm cryopreservation has become the dominant method of fertility preservation for men faced with fertility challenges.2 The process of performing sperm cryopreservation is relatively straightforward. Sperm is classically obtained through masturbation.3 In some cases in which sperm is not possible to be obtained through ejaculation, surgical techniques also exist that may retrieve sperm for cryopreservation.3 The semen obtained is then allowed to liquefy at room temperature and analyzed for motility, concentration, and morphology.3 Following this, many centers will use a selection process such as a swim-up or density gradient centrifugation to identify the most viable sperm within the sample, which is then cryopreserved.3 Cryopreserved sperm are considered relatively stable and may be used even decades later to result in pregnancy.4 Some studies have noted DNA damage to some but not all sperm following cryopreservation.5 However, the safety of using cryopreserved sperm to achieve pregnancy is generally accepted, as decades of healthy pregnancies have resulted from cryopreserved sperm.3,6 Once thawed, sperm may be used to achieve pregnancy either through intrauterine insemination techniques or through IVF. A common indication for sperm cryopreservation is fertility preservation in the setting of cancer. Current recommendations from multiple professional societies recommend that men diagnosed with cancer should universally be offered sperm cryopreservation before initiation of treatment with chemotherapy or radiation that could reasonably impact sperm production.6,7 However, using sperm cryopreservation in

Fertility Preservation Box 1 Available fertility preservation strategies  Cryopreservation Technologies  Sperm Cryopreservation -

Advantages  Easy to obtain in most patients  Excellent results  Long track record

-

Disadvantages  Only possible in male patients

 Embryo Cryopreservation -

Advantages  Excellent results in young patients  Long track record

-

Disadvantages  Requires in vitro fertilization (IVF) to obtain eggs  May be financially costly  Requires female patients to choose sperm donor before cryopreservation

 Oocyte Cryopreservation -

Advantages  Excellent results in young patients  Does not require female patients to choose sperm donor before cryopreservation

-

Disadvantages  Requires IVF to obtain eggs  May be financially costly  Relatively short track record

 Surgical Technologies  Ovarian Transposition -

Advantages  Proven benefit in certain clinical situations  Does not require female patients to choose sperm donor before cryopreservation

-

Disadvantages  Requires surgery  May not have return to baseline fertility potential after radiation

 Uterine Transplantation -

Advantages  Preserves hope of carrying a child for some women in whom uterine function is not adequate to achieve a healthy pregnancy

-

Disadvantages  Requires surgery  Considered experimental at the present time

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 Medical Technologies  Use of gonadotropin-releasing hormone agonists -

Advantages  Not difficult to perform  Relatively inexpensive  Does not require female patients to choose sperm donor before cryopreservation

-

Disadvantages  May not have return to baseline fertility potential after radiation

the setting of cancer therapy is currently underused, with many patients never being offered fertility preservation before oncologic treatment.3 Chemotherapy and radiation treatments have unpredictable impacts on subsequent sperm production.3,7 However, the potential for such treatments conferring a deleterious effect on sperm production and quality is not questioned.3,7 The posthumous use of sperm after fertility preservation also has been described and informed written consent regarding this topic should be obtained at the time of sperm collection for cryopreservation.8 The use of sperm cryopreservation is not exclusive to the setting of cancer. Men with a suboptimal semen analysis may elect to cryopreserve a sperm sample before proceeding with fertility treatments as an “insurance policy” should semen parameters continue to decline in the future. Additionally, the use of donor sperm obtained from large sperm cryobanks is common in the fertility treatment of women wishing to achieve pregnancy in the setting of male factor infertility or when there is no male partner.9 OOCYTE AND EMBRYO CRYOPRESERVATION Available Technology

The first successful report of an IVF procedure was published in The Lancet by Drs Steptoe and Edwards in 1978.10 This procedure is performed by surgically removing periovulatory oocytes from a woman, fertilizing the obtained eggs, and growing resulting embryos in a laboratory environment. Embryo(s) may be then placed in the uterus, resulting in the possibility of pregnancy. Within a decade, techniques designed to achieve multifollicular development of ovarian oocytes in an IVF cycle, a process known as controlled ovarian hyperstimulation (COH), were well described.11 COH allowed women to obtain many eggs during a single IVF egg retrieval.11 This led to experimentation with cryopreserving embryos for use at a later time. By the mid-1980s, pregnancies resulting from the transfer of cryopreserved embryos, a procedure known as frozen embryo transfer, were being reported.12 The process of freezing embryos has become increasingly sophisticated with time. One of the chief dangers involved in embryo cryopreservation is the formation of ice crystals during the freezing process that may cause irreparable damage to cellular structures.13 Consequently, techniques that have been developed for embryo cryopreservation attempt to minimize this phenomenon. Cryoprotective additives are used to dehydrate embryonic cells before cryopreservation, thus reducing intracellular ice crystal formation.12,13 Traditionally, embryos were cryopreserved using a process called slow cooling. Slow cooling uses a low cooling rate of approximately 0.3 C per minute until the temperature of approximately –40 C is achieved, at which point the

Fertility Preservation

rate of cooling is accelerated to approximately 50 C per minute to a goal storing temperature of –100 to –150 C.12–14 Although many centers described success in the slow cooling of embryos, a more recent technique introduced in the early 2000s, known as vitrification, is now widely accepted by many experts as the gold standard for embryo cryopreservation.15 Vitrification uses extremely rapid cooling rates of more than 10,000 C per minute and uses specialized carrier systems (open vs closed).12,15,16 Vitrification accomplishes a near “glasslike” crystal lattice within the cryopreserved embryo, which is thought to dramatically decrease the chances for ice crystal formation.13,17 Embryo survival and pregnancy rates from embryos, particularly at the blastocyst stage, may be superior using vitrification as compared with slow freezing.16 Consequently, a general shift toward increased use of vitrification has occurred in many centers.18 However, some data show that in the right hands, similar outcomes exist with vitrification and slow freezing.19,20 Therefore, the superiority of a single cryopreserving modality remains somewhat controversial. Successful oocyte cryopreservation using slow freezing techniques has been described for several decades.21 However, the rate of survival on thawing oocytes frozen using slow freezing techniques and correlating pregnancy rates were disappointing.13,21 These suboptimal results using slow freezing resulted in classifying oocyte cryopreservation as experimental. Recently, vitrification technology has been applied to oocyte cryopreservation. Pregnancy rates using oocyte cryopreservation using vitrification have been extremely encouraging, and protocols for optimizing this practice are now well described.22 In 2013, the American Society of Reproductive Medicine removed the “experimental” label associated with oocyte cryopreservation.23 After this, the American College of Obstetricians and Gynecologists confirmed that oocyte cryopreservation was no longer considered experimental.24 Oocyte cryopreservation is now considered a mainstream technology that is commonly used under the umbrella of ART and IVF.25 ONCOLOGIC APPLICATIONS

Annually in the United States, more than 130,000 patients are diagnosed with cancer in their reproductive years (up to 45 years), including more than 12,000 children (0– 19 years).26 With modern, comprehensive treatment, the vast majority of children, adolescents, and young adults diagnosed with cancer will become long-term survivors.26,27 Combined with a trend in delayed childbearing, fertility after cancer treatment has become a key quality-of-life issue to many patients (and their parents) in this age group. Unfortunately, fertility in both male and female survivors appears to be compromised, particularly if alkylating agents and/or radiation were administered.28 Among young patients with cancer, the ability to preserve fertility options before gonadotoxic treatment has become of paramount importance.7 For pubertal girls, retrieving oocytes for both oocyte or embryo cryopreservation is valid and should be offered, but it is also time-consuming and necessitates a quick decision when the patient may already be overwhelmed by a multitude of other management issues, including impending cancer treatments. Finally, access to fertility preservation services because of availability and cost is still variable across the United States.7 Fertility preservation via either oocyte or embryo cryopreservation is an increasingly used strategy in the setting of oncology.25 The ovaries have long been known to be exquisitely sensitive to damage from exposure to cancer treatments such as chemotherapy or radiation therapy.29 Damage from these agents has been well

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documented for decades to lead to damage that in many cases results in amenorrhea and the complete failure of competent follicular recruitment and ovulation.29 However, the fecundity rates after significant ovarian exposure to these agents may be significantly lower than background even when menses continue or return.30 Many experts now believe that damage to core mechanisms within the oocytes themselves, possibly on a genetic level, is the cause of these long-term compromised fecundity rates. Some chemotherapy agents, such as alkylating drugs, are known to confer a greater deleterious effect than other agents, such as methotrexate.31 However, the true extent of damage from all chemotherapy agents has not yet been fully described. Similarly, cancer therapies using radiation can exert a deleterious effect, but the extent of this damage is not fully defined. Embryo and oocyte cryopreservation represent an accessible technology with which women may pursue fertility preservation before oncologic treatments. Cryopreserved oocytes or embryos may be used once a cancer-free status is achieved if there is no residual ovarian function after therapy. Sadly, however, cryopreservation strategies in the setting of cancer therapy are currently underused, with many patients not receiving adequate counseling on fertility preservation before oncologic treatment.16,31,32 Recently, opinions from major professional societies state that the current standard of care should include offering fertility preservation to patients faced with oncologic treatment.7,16,31,32 At St Jude Children’s Research Hospital, an increased focus for offering fertility preservation is taking place among adolescent and young adult patients at increased risk for infertility secondary to cancer treatment. Before, during, and even after receiving chemotherapy and radiation treatments for hematologic/oncologic diseases, St Jude patients are now routinely offered a consultation with a boardcertified reproductive endocrinologist from our center. After considering available options, many patients then choose to proceed with fertility preservation through either sperm cryopreservation or through ovulation induction with oocyte cryopreservation. This practice has given hope of retained fertility to many young men and women, and we are optimistic that this sort of progressive program will be adopted by other centers on a large scale. WOMEN WISHING TO PRESERVE THEIR FERTILITY POTENTIAL

For thousands of years, there was essentially no mechanism other than abstinence with which human beings could control the timing of reproduction. This resulted in women undergoing childbearing relatively early in their lives. Today, many perceive this early childbearing to functionally conflict with career advancement for many women. The introduction of oral birth control pills as a form of contraception in the 1960s fundamentally altered this paradigm and afforded women the power to control their fertility and delay childbearing. As a result, the age at which women achieve pregnancy has continually and significantly increased since the 1960s, especially in wealthy nations.33 Unfortunately, fertility potential in women decreases with age, especially after the age of 35. Many women who would be mildly subfertile in their 20s are unable to achieve pregnancy via natural intercourse alone in their mid-late 30s and early 40s.23,34,35 Consequently, the use of ARTs, such as IVF, to achieve pregnancy is relatively common in this age group. However, even with such measures, pregnancy rates per month are low, generally not exceeding 10% per IVF attempt, after the age of 42. Therefore, for many women, delaying childbearing until their late 30s or early 40s

Fertility Preservation

results in a significantly lower possibility for achieving pregnancy with their biological child. The first pregnancies resulting from cryopreserved oocytes and embryos were reported in the mid-1980s.23,36 Although pregnancy rates associated with embryo cryopreservation were encouraging, survival rates of cryopreserved oocytes were generally poor.37 Therefore, for the past several decades, a solution to minimize the effect of maternal age on fertility decline has been to undergo an IVF cycle, cryopreserve embryos, and place these embryos into the uterus at the time pregnancy is desired. Because fertility for the most part is felt to be tied to ovarian age, rather than the age of the uterus, pregnancy rates using this approach were encouraging. A central limitation of embryo cryopreservation, however, is that this approach requires women to choose a male sperm donor to fertilize an oocyte (egg) before cryopreservation. Early attempts to freeze unfertilized oocytes were generally discouraging and not felt to be optimal for fertility preservation by many experts.37 Although embryo cryopreservation did offer a viable option for fertility preservation in some couples, this option was unappealing for some women who did not have a male partner at the time of desired fertility preservation.19 Following the description of excellent pregnancy rates using vitrification techniques to cryopreserve oocytes, dozens of centers began to use this technology on a routine basis. Currently, pregnancy success rates from IVF cycles using oocyte cryopreservation are comparable to fresh IVF cycles, a feat that has been realized only in the past several years.13,22 The ability to efficiently and effectively cryopreserve oocytes has the potential to have a significant social impact over the next several decades. Before this technology, women entering their mid to late 30s electing to defer pregnancy accepted a continually declining age-related fertility potential and the possibility of not ever having their own genetic child. Oocyte cryopreservation empowers women to delay childbearing without committing, at the time of the procedure, to what sperm will be ultimately used for fertilization. Some have compared the ultimate social impact of oocyte cryopreservation to the introduction of birth control pills.25 Oocyte cryopreservation also has other applications. This technology is likely to emerge as a central tool for preserving fertility in young oncology patients who have not initiated or completed childbearing. Additionally, couples undergoing IVF who have ethical or moral objections to cryopreserving embryos may avoid this concern with oocyte freezing. Leading centers around the world now routinely offer oocyte cryopreservation for fertility preservation. Over the past several years, oocyte cryopreservation has become increasingly visible in the public eye. Multiple high-profile celebrities have publically announced that they are pursing or have undergone oocyte cryopreservation for fertility preservation.25 This procedure is appropriate for young women wishing to maximize their future fertility when achieving pregnancy is not desired until the mid to late 30s or beyond. Because the sharpest decline in a woman’s fertility occurs after the age of 35, oocyte cryopreservation is most effective if pursued at a relatively young age, ideally before the age of 30.23,24 In healthy women, it is believed that the average chance of achieving a pregnancy from one mature egg is approximately 5% to 10%.19,38 Therefore, on average, freezing 10 to 12 mature eggs from a young woman generally provides a good statistical chance for achieving pregnancy up to the late 40s. Ultimate pregnancy rates resulting from oocyte cryopreservation are known to most sharply decline after the age of 38.39 Although obtaining this number of eggs is common in young women, some women may require multiple IVF stimulation cycles to “bank” this number of oocytes. Therefore, oocyte cryopreservation cannot ensure future

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fertility. Rather, this strategy serves as an “insurance policy” that could be used if pregnancy with natural intercourse is not achieved at the desired time in the future. Women interested in oocyte cryopreservation are encouraged to discuss the capabilities and limitations of the procedure with a physician specializing in ARTs. COUPLES UNDERGOING IN VITRO FERTILIZATION WITH ETHICAL OR MORAL CONCERNS

Some couples undergoing IVF are concerned about freezing additional embryos that may not be used in the future.24 As an alternative, in the course of an IVF cycle, it is now possible to fertilize fewer oocytes, which could become embryos, while cryopreserving the excess unfertilized oocytes. This approach allows couples to sequentially thaw and fertilize oocytes to generate the number of embryos necessary to achieve their reproductive goals. Excess unfertilized oocytes may then be donated or discarded when the couple’s family is complete. WOMEN WITH CERTAIN GENETIC CONDITIONS

Several genetic disorders have been associated with early ovarian failure. For example, women with fragile X premutation or mosaic Turner syndrome may choose to cryopreserve oocytes while they still have ovarian function. Other genetic mutations, such as the BRCA mutations, are associated with an increased risk of ovarian cancer. Women who elect to have prophylactic salpingo-oophorectomy may choose to cryopreserve oocytes before surgery. OVARIAN TRANSPOSITION

The effects of radiation on fertility are dependent on patient age, dosage, interval between doses, disease type and location, and size of the radiation field. Standard radiation doses are 40 to 50 Gy; however, higher doses are given in total-body irradiation protocols before bone marrow transplantation, as would be required for treatment of recurrent lymphoma or leukemia.40,41 Ovarian failure is seen in more than 90% of patients receiving at least 5 Gy of pelvic radiation.42 Further, scatter radiation from a beam not aimed directly at the pelvis may still impact future reproduction.43 Less extensive radiation fields and minimal doses carry a lower risk of infertility,44 and several studies show that doses less than 5 Gy do not decrease fertility.45–47 However, due to lower ovarian reserve, increasing age at the time of radiation is related to greater gonadotoxicity, just as with chemotherapy. Oophoropexy and ovarian transposition are procedures that change the location of the ovaries in an attempt to remove them from the pelvic radiation field. They differ only in their surgical technique, so herein the terms will be used interchangeably. These procedures may be used to lessen the likelihood of scatter radiation affecting the ovaries in gynecologic as well as colorectal and spinal cancers for which radiation is planned.48 Ovarian transposition may be performed either at the time of laparotomy if one is needed for treatment or may be done laparoscopically in the outpatient setting as an isolated procedure. Oophoropexy can reduce ovarian radiation dose up to 95%.49 Because the ovaries remain on their original attachments, they can migrate back to the pelvis. So, oophoropexy should be conducted immediately before radiation treatment begins.50 If chemotherapy that is not gonadotoxic is planned before pelvic irradiation, the procedure should be performed before initiation of chemotherapy. This is because patients are immunosuppressed on most chemotherapeutic regimens and, therefore, may not be healthy enough to undergo elective surgery.

Fertility Preservation

Ovarian transposition is not indicated if gonadotoxic chemotherapy is planned, because the ovaries will be adversely affected by the medication regardless of their location. After transposition, 60% to 89% of patients with cancer who are younger than 40 maintain ovarian function.50–53 Failures are a result of radiation that scatters to the new ovarian location as well as necrosis of the ovary from compromised blood supply due to transposition, as necrosis can lead to follicular atresia and premature menopause.54–58 Most women retain enough ovarian tissue for endocrine function, but some studies report that only 15% of patients are fertile after ovarian transposition.59 Spontaneous pregnancies have been reported after oophoropexy. However, some patients need either oocyte retrieval with in vitro fertilization or reversal of the procedure because the ovary is no longer in close proximity to the fallopian tube.56,60 Transvaginal oocyte retrieval is more difficult after transposition due to increased distance between the vagina and ovary.56 Transabdominal aspiration may be attempted, but that approach can yield fewer oocytes.49 However, one publication revealed no significant differences between transvaginal and transabdominal aspiration in the number of damaged oocytes, fertilization rates, embryo number and quality, and clinical and ongoing pregnancy rates.61 Additional complications may arise after oophoropexy, such as pelvic pain from ovarian or fallopian tube infarction or cyst formation. Further, ovarian cancer detection by physical examination is more difficult if the ovaries are no longer located in the pelvis.62 Gonadal shielding can reduce the radiation dose to the ovaries if ovarian transposition is contraindicated for any reason, but this technique is possible only with certain radiation fields and requires significant expertise in this area.62 UTERINE TRANSPLANTATION

After a hysterectomy for gynecologic cancer, uterine transplantation as part of a research study is the only way a patient could carry a pregnancy. The first transplantation of a human uterus resulting in patient survival was performed in Saudi Arabia in 2000. Unfortunately, the uterus had to be removed 99 days after surgery due to necrosis from clotting in the uterine vessels.63 Despite this failure, great strides have been made in the area due to advances in antirejection regimens, and the first successful transplantation was performed in 2011 in Turkey.64 The patient conceived in 2013, but the pregnancy failed in the first trimester.65 Also in 2013, 9 Swedish women received uterine transplants and had subsequent menstrual cycles, but there are no reported pregnancies yet.66 Posttransplantation pregnancies have been demonstrated in mice and dogs with birth by cesarean delivery in sheep.67–71 Uterine transplantation is considered investigational in humans at this time, but advances in the field have been significant over the past 2 decades. USE OF GONADOTROPIN-RELEASING HORMONE AGONISTS IN THE SETTING OF ONCOFERTILITY

Radiation and chemotherapeutic agents act on rapidly dividing cells, such as those encountered in malignancies and gonadal germ cells. In female individuals, ovarian primordial follicles and oocytes are particularly sensitive to cytotoxic agents. These germ cell complexes cannot be replenished, and their destruction may lead to premature ovarian failure, a condition commonly referred to as premature menopause. Although age-dependent, up to two-thirds of all women treated for cancer will develop premature menopause.72 Administration of gonadotropin-releasing hormone analogs

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(GnRHa) to suppress pituitary gonadotropins and follicle-stimulating hormone (FSH)-dependent germ cell maturation theoretically would prevent ovarian follicle maturation and destruction. However, the initial differentiation of primordial follicles is not FSH-dependent, thus potentially limiting the protective effect of GnRHa in female individuals. In mouse models, prepubertal status has not been protective against the follicle depletion induced by cyclophosphamide at doses similar to those used therapeutically in humans.73 In female individuals, most prospective studies investigating gonadal protection by GnRHa during chemotherapy were uncontrolled and demonstrated inconsistent results. Almost all have used resumption of menses as the primary outcome. Unfortunately, return of menstruation and ovulation is a poor marker of fertility, as successful gestation requires the release of a robust, high-quality oocyte. It is likely that these high-quality oocytes would be the most susceptible to chemotherapyinduced cytotoxicity.73 Despite these concerns, there is level I evidence supporting the use of GnRHa suppression before chemotherapy to preserve ovarian function. An Italian study randomized 282 premenopausal women with breast cancer to receive chemotherapy with or without triptorelin, a depot GnRHa. One year after chemotherapy, resumption of menses was more likely in subjects using triptorelin with chemotherapy (49.6% vs 63.3%; 95% confidence interval, 1.0%–26.5%; P 5 .03). The investigators calculated that 6 patients needed to be treated with GnRHa to prevent 1 from persistent amenorrhea.74 A meta-analysis of 6 randomized trials concluded in favor of GnRHa cotreatment with higher rates of spontaneous resumption of menses and ovulation. However, there was no demonstrable improvement in pregnancy rate.72 Similarly, another recent meta-analysis of 12 randomized and nonrandomized studies of women with breast cancer demonstrated no benefit in fertility preservation by using GnRHa gonadal protection.75 Although controversial, in children or young women with cancer, some experts recommend the use of GnRHa gonadal protection with initial chemotherapy to increase the probability of retaining ovulation and ovarian function. However, there is no present evidence that this modality will preserve fertility. Affected young women and men should be counseled at the time of diagnosis about other fertility preservation methods, such as gamete cryopreservation, even if they display ambivalence. PSYCHOLOGICAL CONSEQUENCES OF FERTILITY PRESERVATION: MALES

For more than 70 years, sperm cryopreservation has been used as a mechanism to preserve fertility. This intervention has become even more practical and effective with the development of IVF via intracytoplasmic sperm injection. As the use of fertility preservation has increased among at-risk populations (including those diagnosed with cancer), so have the considerations regarding the effects that banking may have on quality-of-life outcomes, including psychological functioning. Men who are younger, more educated, and/or childless are most likely to bank sperm, whereas those with all their desired children or a history of infertility/vasectomy are less likely to bank.76,77 Regardless, fertility preservation in adult men is often associated with a sense of peace and hopefulness for the future even during the period of impending cancer therapy.78–80 Of adult males, 96% would recommend sperm banking to other patients, and banking has been associated with significant psychological relief even if the sample is never used.81 In contrast, those who do not bank and are suspected to have infertility commonly report conflict within intimate relationships, risky sexual behavior, lower self-esteem, and concerns about being rejected by future

Fertility Preservation

partners.82,83 Fertility-related distress is a long-term issue that can impair quality of life for many years after treatment, and banking is one intervention that appears to improve associated psychological outcomes.84 Although sperm banking has become a more common practice among adults, much less is known about fertility preservation among adolescents. Adolescents are less likely to bank than adults; and it appears that higher Tanner stage, history of masturbation, perceptions of fertility risk, communication of fertility risk, recommendations to bank by providers and parents, higher banking self-efficacy, beneficial perceptions of banking, higher socioeconomic status, being diagnosed with a nonleukemia/lymphoma, and self-identifying as nonevangelical all associate (on the univariate level) with banking/attempting to bank sperm among adolescents newly diagnosed with cancer.85,86 Ginsberg and colleagues87 reported that 55% of adolescents and 88% of their parents had favorable initial impression of sperm banking, and that most families reported that the timing of sperm banking communications had been acceptable. One hundred percent of patients and parents responded “Yes” to the question “Did you make the right decision to attempt banking?” including those adolescents who attempted to bank but failed. Finally, 20% of the sample had to delay treatment to bank, but all of these families felt that banking was worth the delay. Finally, adolescents newly diagnosed with cancer were more likely than their mothers and fathers to prioritize fertility as a “top 3” life goal (behind good future health and work/school success), with youths ranking fertility as being significantly more important than future home ownership or financial wealth.88 PSYCHOLOGICAL CONSEQUENCES OF FERTILITY PRESERVATION: FEMALES

Whereas 18% to 31% of at-risk male patients cryopreserve sperm before potentially sterilizing cancer therapy, only 2% to 12% of female patients with similar threats engage in fertility preservation.76,79,85,89,90 Preservation rates may be lower in female patients as embryo cryopreservation is typically used by women in current partnerships. As oocyte cryopreservation was recognized as a safe and effective fertility preservation method by the American Society of Reproductive Medicine only in October of 2012, rates of utilization for this intervention are even lower. Although several experimental fertility preservation methods may be offered, embryo and oocyte cryopreservation are among the few clinically accepted interventions available for female patients at this time to preserve fertility potential. Ruddy and colleagues90 recently reported that 11.6% (72/620) of women within a multicenter cohort study for early-stage breast cancer used fertility preservation with 46 (7%) using embryo cryopreservation, 7 (1%) using oocyte cryopreservation, and 19 (3%) using an experimental GnRHa intervention. Interestingly, the proportion of women who used fertility preservation in this study significantly increased from 5% in 2005 to 15% in 2012. An additional 117 (19%) of these women chose alternative cancer therapies (ranging from refusal of endocrine therapy to choosing one chemotherapy regimen over another) to reduce the likelihood of treatment-related infertility. Psychologically speaking, women are more likely to experience fertility-related distress than men, with risk factors such as history of chemotherapy, younger age, being non-White, and/or being childless placing women at highest risk.90–92 Less is known about fertility preservation in adolescent girls diagnosed with cancer, as the options available to this subgroup have traditionally been extremely limited. Burns and colleagues93 examined interests in fertility preservation (along with willingness to wait 1 month to start therapy) among adolescent girls on treatment for

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childhood cancer and their parents. Among participating families, most adolescents (80.6%) and their parents (93.1%) endorsed interest in oocyte preservation, but only 29% of adolescents and 19.2% of parents were theoretically willing to delay treatment to complete this process.93 As ovarian stimulation and subsequent egg harvesting can now take as few as 10 to 14 days, this intervention is now being offered clinically to adolescent girls. Wallace and colleagues94 recently reported that 21 of 34 families with young daughters at risk for premature ovarian insufficiency (aged 1.2–16.4 years) consented to ovarian tissue cryopreservation, a technique that remains experimental. Regardless of actual risk, parents with children diagnosed with cancer are concerned about potential infertility and are willing to pursue fertility preservation, even within an experimental context.95 SUMMARY

Strategies used to accomplish fertility preservation are many. Over the past several decades, new technologies, especially related to ART and IVF, have greatly expanded ways to accomplish fertility preservation. These advances also have grown the indications for pursing fertility potential in general. Surely, such advances will continue to be optimized in the future. By all indicators, the role for fertility preservation in society and medicine is likely to only increase over the next several decades. REFERENCES

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