Introduction

Gynecologic cancers represent a significant proportion of malignancies most frequently affecting women. In 2010, uterine and ovarian cancers are estimated to be the fourth and ninth most commonly encountered tumors in U.S. women, respectively [1]. Despite the preponderance of such tumors occurring in postmenopausal females, those of reproductive-age are not immune. In fact, 8% of endometrial, 12% of ovarian and 40% of cervical cancers occur in the childbearing years [2].

 

In the past, cancer treatment regimens, regardless of patient age, focused primarily on eradicating disease, irrespective of impact on future fertility and parenthood. This, combined with poorer survival, mandated that quality-of-life issues be secondary. However, early detection and improved treatment protocols, including routine Papanicoloau (Pap) screening, the availability of noninvasive imaging modalities, minimally invasive surgical techniques, and improved antineoplastic and chemotherapeutic agents, have significantly impacted diagnosis and survival statistics for gynecologic cancers. Therefore, life issues, such as fertility preservation (FP) and parenthood after cancer, are now integral components in the selection and execution of treatment plans. In a survey of radical trachelectomy patients, 41% reported that reproductive concerns were important in their choice of treatment [3]. Another survey including patients with all types of cancer (one-half gynecologic) seeking FP in the course of care found that 55% felt having a child was most important in their life (scale 1–7; mean, 6.1) while 64% were most concerned with the impact cancer treatment would have on fertility (mean, 6.1) [4]. In response to patient desire and oncologic advancements, the arena of FP has expanded substantially in recent years. This manuscript reviews normal female reproductive function as well as the natural and treatment-induced compromise that occurs when managing gynecologic malignancies. In addition, it assesses current FP treatment options available to women diagnosed with these diseases.

Reproductive function and oocyte decline

Oocytes

Gametogenesis in the female, in contrast to the male, is a limited event. The process of oogenesis begins before birth with a peak in oocyte number (6–7 million) at 20 weeks of gestation. By birth, this number abruptly drops to 1–2 million, and at puberty only ~ 400,000 oocytes remain. The precipitous drop in gamete number is due to oocyte atresia, a process that is constantly ongoing until menopause, regardless of pregnancy, amenorrhea or contraceptive use; importantly, the rate of atresia dramatically increases in the later reproductive years, eventually culminating in menopause.

Oocytes in the prepubescent period are arrested in meiosis I, as primordial follicles. These immature follicles are relatively small (containing less fluid), making them potentially more resistant to gonadotoxic therapy. Once puberty ensues, a monthly cohort of follicles is selected to grow, develop, and re-enter the cell cycle; however, only one will mature, undergo ovulation and complete meiosis I (Fig. 1).



Fig. 1. 

In addition to the progressive decline in oocyte number that naturally accelerates in most women from age 30 to 50, there is a significant diminution in oocyte quality. As a result of this combined phenomenon, women become significantly less fertile during the latter reproductive years. Recent data from Edinburgh demonstrated that by age 30, only 10%, and by age 40, only 3% of a woman's oocytes remain [5]. However, despite these alarming statistics, the majority of women will continue to ovulate and menstruate well into their late 40s. Traditionally, in both medical literature and clinical practice, menses has been mistakenly equated with the ability to successfully conceive. Therefore, studies utilizing return of menses as a marker of FP following cancer treatment must be regarded with reservation. Globally, reproductive trends have been grossly altered as a result of assisted reproductive technologies (ART), thereby coloring the public's interpretation of fertility and age. For instance, most conceptions occurring beyond the age of 45 are through the use of donor oocytes (where healthier oocytes of another woman are used to create the pregnancy). A great deal of information regarding natural fecundity rates can be ascertained by reviewing classic studies of populations, such as the Hutterites, that traditionally refrained from birth control and ART. In the 1950s, the average number of births per Hutterite woman was 9.8 [6]. However, even in this incredibly fertile population, the average age at last birth was 40.9 years. Data from these women demonstrated a sharp linear rise in infertility; 11% at age 35, 33% at age 40, and 87% at age 45 (despite continued menses). These data highlight two important points for both the female cancer patient desiring fertility potential and the treating provider; first, the optimal age at which to preserve fertility is dictated by oocyte quality and quantity, and thus, it is best when performed at a younger age if possible and, second, even though fertility potential diminishes with age, the ability to conceive can persist into a woman's mid-forties and therefore must not be overlooked, even at this point.

Uterus

Although the ovaries are “time-sensitive,” the uterus is resilient and does not appear to be significantly affected by age. Data from donor oocyte literature demonstrate that recipient age is not predictive of pregnancy outcome [7] and that women who have clearly surpassed menopause, despite the number of years, can have successful pregnancies. In fact, worldwide, at least 7 women over the age of 64 have given birth following the use of donor oocytes. Thus, although oocytes from woman over the age of 45 rarely result in conception, implantation at the uterine level is not limited by age. Therefore, the decision whether to remove the uterus in the management of gynecologic malignancies warrants thorough discussion.

Cervix

Similar to the uterus, the cervix–and its ability to contribute to a successful pregnancy–is not impacted by a woman's age. During ovulatory menstrual cycles, mucous is secreted by endocervical glands in response to elevated estradiol levels theoretically serving as a reservoir for sperm and improving the likelihood of fertilization and subsequent pregnancy. Interestingly, pregnancies are routinely achieved in women who have undergone cervical trachelectomy for early-stage cervical disease [8], although the need for ART is increased in this patient population. Promising and rapidly accumulating data in post-trachelectomy patients underscore the need to consider fertility-sparing surgery in carefully selected patients of reproductive-age who are desirous of future childbearing.

Ovarian reserve (OR) evaluation

When considering FP, an integral component of the patient's evaluation must include appraisal of her ability to conceive. This is most often achieved through an assessment of “ovarian reserve” (OR) (Table 1). The most important OR assessment is patient age; it is well known that fertility declines after age 28 and more rapidly beyond age 35, but individual fertility potential is known to vary substantially from woman to woman, particularly in the later reproductive years. Thus, it is difficult to assign the exact age at which FP efforts are futile, although most experts agree that success will be limited after the age of 43, and higher before the age of 40. In addition to age, OR can be measured using a variety of serologic and ultrasound examinations routinely performed by a reproductive endocrinologist in an outpatient setting. The most widely utilized and accepted assessment is the measurement of early follicular (menstrual cycle day 2 or 3) serum hormone levels, specifically follicle stimulating hormone (FSH) and estradiol. If possible, these two hormone levels should be measured concordantly as estradiol, via negative feedback, is known to inhibit FSH secretion. Thus, FSH can be measured spuriously low in the presence of elevated estradiol, misleading the patient and/or treating clinician to believe the patient is more fertile than is true. In fact, both elevated FSH [9] and [10] and/or estradiol [11] measured in the early part of the menstrual cycle are not only indicative of diminished OR but also of a substantially reduced ability to conceive. Two additional serologic measurements, anti-Müllerian hormone (AMH) and inhibin-B, have also been demonstrated to correlate with OR [12] and [13], although these two assays are used less commonly than FSH and estradiol. AMH is secreted by granulosa cells of antral (developing) ovarian follicles; reduced AMH levels are associated with decreased OR [14]. One advantage in using AMH is that this test can be performed at any point during the menstrual cycle i.e., it is (not limited to the early follicular phase), as it has minimal inter-cycle variability. This makes it increasingly appealing for time-constrained cancer patients. Inhibin-B is part of a protein complex secreted throughout the menstrual cycle and known to function in the down-regulation of FSH synthesis and secretion [15]. In normal fertile women, a rise in inhibin-B is paralleled by a decline in FSH throughout the follicular phase. Therefore, lower early follicular levels of inhibin-B not only correlate with higher FSH levels but also forecast diminished OR [12]. Inhibin-B testing is generally reserved as a confirmatory marker of poor ovarian reserve when FSH testing is questionable and thus is not routinely used to evaluate whether a cancer patient is a candidate for FP procedures.
 

In addition to serologic OR assessments, simple, noninvasive sonographic evaluations are available that can help assess a woman's ovarian function. Such examinations include measures of ovarian volume, antral follicle count, and ovarian peak systolic velocity. Ovarian volume is known to decrease throughout the peri-menopausal period [16]. This, combined with available ovarian volume data in women of reproductive-age, suggests that its decline is a harbinger for diminished OR [17]. Furthermore, a decline in ovarian blood flow, as measured by Doppler ultrasound, has also been associated with reduced ovarian competence [18]. Although sonographic OR modalities are less predictive than serum assays, they can serve as an important adjunct not only to a complete assessment of OR but also the appropriateness of a patient's candidacy for fertility preservation. In addition, sonographic ovarian assessment can aid the reproductive endocrinologist in choosing an optimal FP medication regimen. For instance, women with polycystic ovarian syndrome (PCOS; often found in patients with endometrial malignancies) tend to be higher responders to fertility medication and need to be dosed down to avoid ovarian hyperstimulation syndrome. Therefore, these exams, combined with patient age, preference, and disease status, collectively guide the direction of a patient's future fertility treatment.

Cancer treatments affecting fertility and pregnancy

Surgical removal of key fertility organs

Surgical resection of disease is a crucial component in the treatment of gynecologic malignancies and generally includes removal of the uterus, cervix, fallopian tubes, and ovaries. In addition, ovarian and uterine cancers are staged surgically and therefore pathologic assessment of these organs is necessary to determine prognosis and guide recommendations for adjuvant therapy. However, in carefully selected patients having a strong desire for future fertility (Table 2), staging and therapeutic surgical procedures can be modified in order to maintain organs necessary for reproductive function. Some examples include: the use of progestional agents in early-stage endometrial cancer, trachelectomy in early-stage cervical cancers, and uterine and contralateral ovarian preservation in good-prognosis ovarian tumors. Furthermore, ovarian preservation in early-stage endometrial and cervical cancer should be considered as this practice will not only maintain fertility but also endocrine function. Endogenous ovarian estrogen production serves several protective functions and thus, when appropriate, ovarian conservation should be considered. A detailed counseling session, even in a motivated patient, is crucial to the success of these techniques.
 

If carrying pregnancy post-treatment is to be considered, the uterus, with or without its cervix, must be maintained. In vivo ovaries are not necessary during the gestational period as all essential ovarian hormones can be exogenously administered. In addition, once placentation is complete (~ gestational weeks 10–12), hormonal supplementation can be discontinued. If the ovaries need to be resected, gamete and/or embryo cryopreservation prior to removal should be considered to allow the opportunity for a biologic offspring.

Chemotherapy

Chemotherapy can be detrimental to ovarian competence, devastating a woman's future fertility potential by damaging oocytes. The extent of damage is dependent on three factors: medication, drug dosage, and patient age. The type of medication is the most important factor in determining the incidence of ovarian failure. For example, alkylating agents, such as cyclophosphamide, are high-risk and therefore have the greatest chance for inducing amenorrhea. These agents in the past were used in the primary treatment of ovarian cancer and more recently have been advocated in the treatment of gestational trophoblastic disease. Moderate risk agents, which include the platinums, taxol and doxorubicin, are also commonly employed in the treatment of gynecologic malignancies. Although most female human data designates the fertility risk associated with these drugs as moderate, newer data from animal studies suggest these drugs might impart more gonadal toxicity than was previously thought. Additional controlled studies are needed to clarify the impact individual agents have on future fertility. In the interim, such findings demonstrate the importance of providing fertility preservation counseling to all reproductive-age women with cancer irrespective of the chemotherapeutic regimens they are scheduled to receive.

Patient age also plays a significant role in the risk of ovarian failure. As described above, female gametogenesis ceases to occur after 20 weeks in utero, and therefore as a woman ages, the number of available follicles consistently declines. Thus, older patients are at greatest risk for developing ovarian failure from chemotherapy. In contrast, prepubertal girls, with a greater primordial follicle reserve, are more resistant to the sterilizing effects of chemotherapy. This phenomenon is best demonstrated in breast cancer patients where more than 50% of patients over the age of 40 experience ovarian failure compared to 30% in those less than age 35 [19]. Lastly, medication dosage must be considered when evaluating a patient's risk for developing ovarian failure. Higher dosages of medications, particularly those considered high-risk, have a greater likelihood of inciting ovarian compromise. Decreased ovarian reserve and higher baseline follicular FSH levels, even in young cancer patients are indicative of accelerated oocyte atresia and decreased oocyte quality. Therefore, after administration of chemotherapy, reproduction rates can be significantly reduced [20].

Despite the risk of chemotherapeutic agents on ovarian function, maternal morbidity does not appear to be increased in the majority of pregnancies of female cancer survivors. However, certain agents can have lasting effects on specific organ systems and may result in pregnancy complications (Fig. 2). The untoward effects of chemotherapy on pregnancy outcome cannot be globally classified. Therefore, potential side effects must be addressed on a drug-by-drug basis. Cardiovascular complications, such as arrhythmias, dilated cardiomyopathy, and coronary artery vasospasm (myocardial infarction and angina) are some of the most frequently encountered following the use of anthracyclines (danuorubicin, doxorubicin, idarubicin, epirubicin and mitoxantrone). For those patients with a history of receiving such medications and desirous of pregnancy, a baseline preconception electrocardiogram and echocardiogram should be performed. Some even advocate performing a radionucleotide angiocardiogram and 24-hour Holter monitoring. Carrying a pregnancy should be discouraged if there is a significant reduction in ventricular function (ejection fraction < 40%) [21]. Bleomycin, a drug which is routinely administered for the treatment of germ cell tumors in young girls, can result in pulmonary fibrosis. Pregnant women have an increase in minute ventilation, tidal volume, and oxygen consumption coupled with a decrease in functional residual capacity, putting them at risk for hypoxemia at baseline. If this is combined with pre-existing pulmonary disease, the patient could be at significant risk for hypoxemia which not only has untoward maternal complications but also fetal risks (preeclampsia, intrauterine growth restriction, low birth weight). Therefore, those with a history of receiving such a medication should be screened pre-pregnancy using pulmonary function tests and, if abnormal, followed closely throughout gestation. Importantly, platinums, commonly employed in the treatment of many malignant processes affecting children and young adults and the most common chemotherapeutic agent used in the treatment of gynecologic malignancies, can be nephrotoxic. Although the majority of renal complications associated with the administration of these drugs are acute and therefore no longer an issue once pregnancy is attempted, a small percentage of patients suffer chronic renal insufficiency. Because pregnancy can worsen pre-existing renal conditions depending on baseline function, it would be prudent to obtain baseline laboratory testing (i.e., serum metabolic panel and possibly a 24-hour urine collection) to evaluate kidney function prior to conception. In addition, women with underlying kidney disease are known to have an increased incidence of pregnancy complications such as preeclampsia, intrauterine growth restriction, preterm delivery, and stillbirth [22]. Likely because of the use of ART to achieve pregnancies in cancer patients, an increased incidence of multiple births and delivery by cesarean section have been demonstrated [23]. Therefore, increased maternal and fetal surveillance, including referral to a perinatologist skilled in caring for such patients, is recommended.



Fig. 2. 

Radiation

As opposed to chemotherapy, radiation therapy has been shown not only to have potential deleterious effects on the ovaries but also the uterus and hypothalamic–pituitary axis. Abdominal–pelvic and total body irradiation cause a dose-related reduction in the ovarian follicular pool; however, the magnitude is age-dependent. For example, a mathematical model demonstrated that there is an inverse relationship between age and the radiation dosage required to damage ovarian reserve/function [24]. In addition, a single-dose of radiotherapy appears to be more toxic than fractionated doses. The effect of radiation on the uterus is threefold. First, the uterine vasculature can be damaged, impairing future cytotrophoblast invasion which ultimately can decrease fetal-placental blood flow causing fetal growth restriction [25]. Second, radiation can cause myometrial fibrosis; reduced uterine elasticity and volume can lead to preterm labor and delivery. Lastly, radiotherapy has the potential to injure the endometrium, preventing normal decidualization and interfering with placental attachment. Disorders such as placenta accreta and percreta can subsequently arise [25] and [26]. Therefore, it is recommended that pregnant women who have received pelvic or abdominal radiation be considered high-risk and therefore be evaluated pre-conception and monitored closely throughout gestation. This may include ultrasound and/or MRI to fully assess placentation, serial growth ultrasounds to ensure adequate fetal growth, and antenatal testing to ensure fetal wellbeing. Although there is an increased incidence of preterm birth in these patients, currently there is no reliable screening test or means to predict this event, and therefore practitioners caring for such patients must rely on clinical judgment. Chest and mantle radiation can lead to cardiac complications such as pericarditis, pancarditis, cardiomyopathy, valve injury, and conduction delays [27] and [28]. Therefore, it is recommended that women who have received such treatments have an electrocardiogram and echocardiogram before initiating pregnancy. If an abnormality is detected, referral to a cardiologist and perinatologist trained at caring for such patients is recommended as this patient will likely require intensive antepartum and intrapartum monitoring.

The incidence of congenital anomalies following chemotherapy and radiation has been reviewed on several occasions as cancer patients often report fear of increased risk of congenital and structural anomalies in their offspring as the primary reason for abstaining from pregnancy following a cancer diagnosis [29]. Although no increased risk has been demonstrated [30] and [31], concern is justified because agents used to treat cancer are designed to interfere with DNA, cell division, and cellular metabolism, processes essential to embryo and fetogenesis. In addition, the sex ratio of fetuses born to cancer survivors after treatment as compared to the general population has been reviewed and no differences were noted, supporting the notion that cancer treatment does not cause an increased incidence of X-linked mutations [32]. Lastly, with the exception of cancers that arise secondary to inherited syndromes (FAP, HNPCC, retinoblastoma, Li–Fraumeni syndrome, etc.), there does not appear to be an increase in childhood malignancies in the offspring [33].

Fertility preservation options

Embryo and oocyte cryopreservation

In addition to surgical modifications which aim to preserve organs essential to the achievement of fertility, there have been significant advancements in the arena of ART geared towards helping female cancer patients maintain fertility in the face of cancer diagnoses. Two of the most commonly employed and highly successful technologies are embryo and oocyte cryopreservation. Noyes et al. reported on the use of oocyte cryopreservation in 50 cancer patients as an effective means of FP either preceding or during treatment of their cancer [34]. While the use of both oocyte and embryo storage procedures as FP measures in women diagnosed with cancer is relatively novel, both technologies have been in existence for more than two decades. Embryo cryopreservation has been available as a corollary to in vitro fertilization (IVF) since 1984, when the first successful human live birth using the technology was reported [35]; since its inception, more than 200,000 babies have been born following the transfer of previously frozen human embryos, ensuring, this procedure's feasibility and relative safety. On the other hand, although the first successful live birth resulting from frozen oocytes lagged only two years behind that of frozen embryos [36], reproducibility of the technology was not immediate due to the oocyte's innate fragility and instability, limiting utility of the procedure and deterring its advancement for over a decade. Then, significant developments in Italy led to two series reports of live births following oocyte cryopreservation in 1998 [37] and [38]. These developments marked the initiation and growth of the field of oocyte cryopreservation. A decade later, data suggest that oocyte cryopreservation outcomes can now compare to those of conventional IVF [39], [40] and [41]. In addition, a recent review reporting the outcome of over 900 babies born from oocyte cryopreservation demonstrated no increase in congenital anomalies as compared to natural conceptions [42]. Although the American Society of Reproductive Medicine (ASRM) still considers oocyte cryopreservation experimental, they support its use as a means to preserve fertility in cancer patients [43]. Even though both embryo and oocyte cryopreservation offer cancer patients a viable means to preserve their fertility (with cycle success rates ranging from 30% to 60% in centers adept at the technologies), oocyte cryopreservation appears to be the more appropriate and appealing modality for single women who desire biologic offspring in the future. Oocyte cryopreservation does not require the use of donor sperm (if no partner exists) and thus offers reproductive autonomy. In addition, it eliminates a potentially difficult decision regarding embryo disposition in the event the patient does not survive her malignancy.

For patients who desire FP treatment prior to initiating cancer therapy, oocyte and/or embryo cryopreservation are currently the most widely utilized and recommended modalities. These treatments can be performed expeditiously, requiring approximately 2 to 4 weeks. The range in timing estimation takes into account the patients menstrual cycle (assuming the uterus is present); the use of oral contraception obviates any delay in treatment as ovarian stimulation can be initiated at almost any point during the pill usage. In addition, the patient's “reproductive clock” can be reset with a 4- to 6-day combination of oral contraceptives plus GnRH antagonist or GnRH antagonist alone. Recently, Stanford's group [44] reported no significant difference in the timing of cancer treatments when comparing breast cancer patients who did and did not undergo FP. Noyes et al. [34] demonstrated the average length of fertility preservation treatment time to be 12 ± 0.3 days. Reproductive-age endometrial cancer patients are often ideal candidates for cryopreservation procedures. Even if uterine preservation is not possible, a gestational carrier can be used to carry a pregnancy in the future. Endometrial cancer can be associated with polycystic ovarian syndrome (PCOS) and these patients often respond robustly to ovarian stimulation, producing a high number of oocytes even into the early fourth decade of life. Although currently no substantial evidence exists regarding the effect of ovarian hyperstimulation on disease, it is our belief that these patients can safely undergo fertility treatment. In addition, in patients who have had successful regression of their cancer after conservative treatment, options include spontaneous conception, ovulation induction ± intrauterine insemination, or IVF (using either fresh or previously cryopreserved gametes or embryos, if applicable). In the case of cervical malignancy, where radical hysterectomy ± ovarian transposition is a possibility, oocyte harvest should be considered prior to definitive surgery as hysterectomy can compromise ovarian function [45] and oocyte harvest is more challenging after transposition. Lastly, in ovarian cancer patients, following the initial surgery/staging, oocyte harvest can be considered if either gamete remains in vivo and needle aspiration does not pose a risk of worsening disease.

Use of donor oocytes or a gestational carrier

In the event that a patient is without the time necessary to achieve ovarian stimulation necessary for either embryo or oocyte cryopreservation, or has already received gonadotoxic chemo and/or radiotherapy rendering her infertile, but has retained her uterus, oocyte donation offers a viable option for achieving pregnancy. In this event, another woman donates oocytes (from an anonymously or as a known/related donor) after undergoing ovarian stimulation; once harvested, oocytes are inseminated with sperm, producing embryos which can then be used to create pregnancy. In fact, the Society for Assisted Reproductive Technologies reports a 55% national live birth rate following the transfer of embryos created from fresh donor oocytes [46]. Lastly, in patients whose uterus has been removed or future pregnancy is contraindicated, a gestational carrier can be used to carry a pregnancy for the patient, regardless of the oocyte's origin.

Ovarian transposition

Ovarian transposition is often used in the treatment of cervical cancer where radiation therapy will or may become necessary postoperatively. Issues for FP after transposition include switching from a transvaginal to transabdominal approach for monitoring and oocyte harvest, the latter sometimes resulting in the retrieval of fewer oocytes.

Pelvic radiation is routinely given in cervical, vaginal, and occasionally endometrial carcinomas. A standard dose often induces ovarian failure. Transposition, which involves moving the ovaries above the pelvic brim and out of the radiation field, can reduce the incidence of premature ovarian failure. In fact, correct placement can reduce radiation exposure to the ovaries down to 5–10% of non-transposed ovaries. However, the success of such procedures depends on several variables such as the degree of scatter radiation, vascular compromise, the age of the patient, the dose of radiation, whether the ovaries were shielded, and whether concomitant chemotherapy or vaginal brachytherapy was used. However, although it has been relatively effective at preserving endocrine function in young women, its effect on FP has been limited. Furthermore, the ovaries can migrate back to their original position before radiotherapy. Therefore, the procedure should be performed as close to the radiation therapy administration as possible. In addition, when ovaries are transposed to an abdominal position, spontaneous pregnancy is usually not possible unless a second procedure relocating the ovaries back to the pelvis or IVF (with a transabdominal oocyte retrieval) is performed. In the latter case, as mentioned, oocyte retrieval can be technically more challenging.

Gonadotropin releasing-hormone (GnRH) agonist for ovarian protection

The use of a GnRH agonist to protect the ovaries from the gonadotoxic effect of chemotherapy has been advocated by some clinicians [47], [48], [49] and [50]. In general, the agonist is administered beginning 1 month prior to the initiation of chemotherapy at a variable dosage (3.75 mg monthly to 11.25 mg every 3 months). If any, we recommend the 3.75 mg monthly dosage, as it can be discontinued in the case of drug intolerance and/or if fertility preservation is indicated. The larger 3-month dosage makes immediate ovarian stimulation difficult-to-impossible until the medication effects have subsided, sometimes 4 months after injection.

There are several theories surrounding how this treatment may afford ovarian protection with the most popular and widely accepted described by Blumenfeld: gonadotoxic chemotherapy destroys ovarian follicles resulting in FSH elevation; the elevated FSH enhances the recruitment of primary/quiescent follicles; these follicles re-enter the cell cycle (at a susceptible stage of development) and are further destroyed by chemotherapy. GnRH agonists suppress the pituitary secretion of endogenous FSH/LH, thereby decreasing the accelerated oocyte atresia seen after the administration of gonadotoxic treatment [48]. Unfortunately, large, randomized, controlled trials with adequate follow-up comparing pregnancy rates after cancer treatments with and without agonist are lacking. In addition, available data (in Hodgkin's patients) is weakened by the use of historic controls or by inconsistent comparison groups (e.g., comparing patients with varying stages of disease receiving differing chemotherapeutic agents) [51]. Although Huser et al. [49] did demonstrate a protective effect from the use of a GnRH agonist in conjunction with specific chemotherapeutic agents, there was no statistical difference in the rate of premature ovarian failure after the administration of aggressive chemotherapy (BEACOPP) with or without a GnRH agonist, the group most likely to be considered for such protective treatment. In contrast, a recent randomized trial comparing the return of menses and ovulation in cyclophosphamide-treated women with early-stage breast cancer ± GnRH agonist demonstrated a significant increase in menses resumption and ovulation when GnRH agonist had been added [50]. However, before recommending the use of a GnRH agonist to preserve fertility, patient age, baseline ovarian reserve, oncologic treatment protocol, and social situation (single vs. partner) should be considered. It is our opinion that ideal candidates for this particular FP option are prepubescent girls with a healthy baseline ovarian reserve who will receive treatment known to jeopardize ovarian risk. Having stated that, additional studies proving the benefit of GnRH agonist co-administration are necessary before its use can be universally advocated.

Conclusion

Medicine is a dynamic process with a constant evolution in the ability to diagnose, treat, and cure diseases. In the field of gynecologic oncology, effective treatments can unfortunately come at the price of a woman's ability to conceive and carry a child. Therefore, as we succeed in our fight against previously untreatable malignancies, the population of cancer survivors grows and the loss of fertility becomes a crucial component to a survivor's quality of life. The field of oncofertility–a discipline comprised of surgeons, medical and radiation oncologists, reproductive endocrinologists, perinatologists, and psychosocial support professionals–must continue to move forward to ensure that all patients are afforded the opportunity to maintain their reproductive potential and are given the chance to achieve the most basic desire: parenthood.

Conflicts of interest/disclosure statement

The authors have no conflicts of interest to declare.