INTRODUCTION — Some treatments for malignancy, medical disorders, or gender affirmation can permanently impair reproductive function. Patients considering such therapies should be counseled about their options for preservation of fertility and, if appropriate, potential preservation of ovarian hormone production. Gonadotoxic treatments include chemotherapy, radiation, and surgical resection (for treatment of disease or gender affirmation surgery). However, with appropriate pretreatment planning and intervention, biologic parenthood is possible.
This topic will provide an overview of established cryopreservation techniques to preserve fertility, discuss the possible role of medication to preserve production of ovarian hormones, and discuss interventions to reduce the impact of radiation. The approach to fertility preservation for individuals who wish to delay childbearing and the fertility treatments themselves are discussed separately.
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-diverse individuals.
RAPID REFERRAL FOR COUNSELING — Clinicians should discuss the risk of treatment-induced infertility as well as possible interventions to preserve fertility and hormone production prior to initiating gonadotoxic therapy or extirpative surgery (table 1 and table 2) [1-6]. This discussion should occur as soon as possible during treatment planning because some interventions require time and could delay the start of therapy. Whenever possible, all patients of reproductive age with newly diagnosed cancer and fertility concerns should meet with a reproductive endocrine and infertility specialist. Some institutions provide rapid consultations within 48 hours of diagnosis. Patients who are ambivalent or uncertain about their fertility desires should also be referred . Despite guidelines advocating for fertility counseling for these patients, studies have reported both low provider awareness and variable referral rates for fertility counseling globally [7-10].
There are no large randomized clinical trials evaluating the majority of the interventions described below, nor are there long-term follow-up studies assessing the possible impacts of fertility treatment on cancer survivors. Many oncologists remain cautious about the use of traditional assisted reproductive technology (ART) in women with estrogen-dependent malignancies since ART involves ovarian stimulation and results in high estrogen levels if letrozole is not used during ovarian stimulation. However, based on limited data, ART use in patients with hormone sensitive cancers appears reassuring .
In addition to this topic, the following topics may be useful for patient counseling:
ASSESS PATIENT GOALS FOR THERAPY — When considering reproductive function, one must separately address the patient's desires for future pregnancy and potential preservation of hormone production. Cryopreservation of embryos or gametes is the established method of fertility preservation for adults and postpubertal children (table 3) [2,12]. Separately, in some women, use of gonadotropin-releasing hormone (GnRH) agonists to suppress ovarian function during chemotherapy has been associated with posttreatment return of ovarian hormone production and some live births. However, the live birth rate following GnRH agonist treatment is lower than that from proven assisted reproductive techniques. Suppressive hormone therapy does not appear to preserve fertility for men. For prepubertal children, investigational techniques include possible ovarian or testicular tissue cryopreservation. (See 'Ovarian hormone preservation' below and 'Cryopreservation' below.)
Fertility preservation requires individualization. The optimal approach depends upon the planned treatment (radiation, surgery, chemotherapy, or combination), time available, patient age and pubertal status, the specific disease, partner availability, cost, and consideration of long-term future issues such as storage, use, and disposition of frozen embryos, cells, or tissue. Our approach to decision-making in patients with cancer is shown in the algorithm (algorithm 1). The American Society of Clinical Oncology (ASCO) and the American Society of Reproductive Medicine (ASRM) have published similar recommendations [2,12].
Cryopreservation — Established techniques for fertility preservation include freezing (cryopreservation) of embryos, oocytes, and spermatozoa (table 3) [2,6,12,13]. These cryopreservation techniques are associated with the greatest likelihood of successfully generating offspring. Sperm cryopreservation is a well-established technique that should be offered to all postpubertal boys and adults undergoing gonadotoxic treatment or gender affirmation surgery that involves orchiectomy.
Cryopreservation of reproductive tissues, rather than gametes or embryos, is a relatively newer technology.
●Testicular tissue – Cryopreservation of testicular tissue is available in a few centers around the world and offered only as part of a research protocol [12,15]. A proper technique of testicular tissue transplantation has not yet been established and there has not been a report of successful testicular tissue transplantation in patients. For prepubertal children, freezing of ovarian or testicular tissue is the only fertility preservation option available. These techniques are presented in detail separately. (See "Fertility preservation: Cryopreservation options".)
The presence of cancer probably does not affect ovarian reserve or responsiveness to gonadotropins prior to gonadotoxic therapy, but data are conflicting. While some studies reported decreased number of mature oocytes available for cryopreservation in cancer patients compared with matched controls [16-24], subsequent studies reported that most malignant diseases did not appear to affect ovarian response in cancer patients [25,26]. In some studies, cancer grade is demonstrated to have a negative impact on fertility preservation outcome and ovarian stimulation response  but it is not clear whether this is related to the disease process itself or the impact of the disease on overall wellbeing.
Other methods to preserve or restore fertility
●Radical trachelectomy – In properly selected women with cervical cancer, radical trachelectomy is an option instead of hysterectomy and preserves the uterus for future childbearing. (See "Fertility-sparing surgery for cervical cancer".)
●Hormonal therapy for early stage endometrial cancer – In some selected young patients with early-stage endometrial cancer wishing to preserve the uterus, hormonal therapy using progestins alone or in combination with progesterone-bearing intrauterine systems does not seem to affect survival rates compared with primary surgery [28-30]. (See "Fertility preservation in patients with endometrial carcinoma".)
●Egg donation – If the patient has no fresh or frozen oocytes or ovarian tissue available, but her uterus is intact, fresh or frozen donor oocytes and her partner's sperm can be used for in vitro fertilization (IVF). This is a proven approach, with success rates exceeding 60 percent per embryo transfer. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'.)
Several commercial egg banks are available in the United States. Through 2012, almost 9000 frozen donor oocytes from commercial egg banks were used for IVF, resulting in 602 pregnancies with a clinical live birth rate of 40.5 percent [31,32].
●Embryo donation – Couples in IVF programs sometimes donate their excess cryopreserved embryos, and these embryos can be implanted in a woman with a uterus even if she has no ovarian function. (See "In vitro fertilization: Overview of clinical issues and questions".)
●Gestational carrier – A gestational carrier (ie, surrogate) is a woman who agrees to carry a pregnancy for another woman (intended mother). The intended mother provides the egg, and the intended father provides the sperm; rarely, egg donors or sperm donors are involved. IVF is used to create an embryo, which is transferred into the uterus of the gestational carrier . The gestational carrier has no genetic connection to the embryo. Use of a gestational carrier is an option for women who have undergone hysterectomy but can provide their own oocytes, either fresh or frozen. (See "Gestational carrier pregnancy".)
●Adoption – Adoption is another option for parenthood and is discussed elsewhere. (See "Adoption".)
●Uterus transplantation – Uterus transplantation is an investigational technique being developed for women who have a nonfunctioning or absent uterus. (See "Uterus transplantation for absolute uterine factor infertility: Ethics, patient selection, and consent".)
OVARIAN HORMONE PRESERVATION
Our approach — For women who desire fertility preservation, we offer established cryopreservation techniques. We do not use gonadotropin-releasing hormone (GnRH) agonists for primary fertility preservation since these medications have not been associated with improved pregnancy or live birth rates [2,6,12,34]. (See 'Fertility preservation' above.)
For women who desire only potential preservation of ovarian hormone production, such as those premenopausal women who have completed childbearing, or women in whom established cryopreservation procedures are not an option (due to access, timing, cancer-specific reasons, or patient issues), some practitioners, but not the authors, discuss GnRH agonist treatment to suppress ovarian function . If used, GnRH agonists are coadministered during treatment in an attempt to reduce the risk of chemotherapy-induced ovarian insufficiency. We believe offering this option "just in case" or in addition to established methods is counterproductive, as we observed that, in practice, it tends to replace effective strategies. GnRH agonists cannot replace established methods of fertility preservation and have theoretical risks. In addition, GnRH agonist therapy is not used for preservation of testicular hormone production.
Our approach is informed by the studies and consideration of the issues presented below.
Medical rationale — For premenopausal women undergoing gonadotoxic therapy or surgery, the rationale to attempt to preserve ovarian hormone function is extrapolated from women with premature ovarian insufficiency (POI; ie, menopause at age less than 40 years). In this surrogate population, early loss of reproductive hormones is associated with increased long-term risks of bone loss and osteoporosis, cardiovascular disease, and mortality. Thus, medical therapy to protect ovarian hormone function may benefit younger women receiving gonadotoxic drugs, although long-term supporting data for this specific population are lacking. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)
Role of GnRH agonist — Numerous agents have been shown to cause ovarian injury (table 1). GnRH agonists suppress ovarian function and, therefore, have been theorized to protect the ovary in the setting of a toxic insult such as chemotherapy. However, the ovarian follicles are still exposed to these DNA-damaging agents even though the ovarian hormone production is suppressed. As primordial follicles do not express gonadotropin receptors, it is unclear how GnRH agonist therapy would enhance survival of these cells, if at all .
Limitations — The efficacy of GnRH therapy for preservation of fertility and/or ovarian function is difficult to assess because many studies have used unreliable or unsuitable surrogate outcomes. In addition, most of the studies have assessed the treatment in populations that included multiple different diseases or different stages of one disease. The ultimate measurement of fertility is live birth rate. However, the number of live births in these studies is often small, and statistical assessment is limited by sample size. Other markers associated with reproduction and ovarian function are often reported, but these surrogate outcomes are not necessarily predictive of live birth rate. For example, resumption of menses is a poor predictor of fertility because women can resume menses but remain infertile. In addition, these studies do not report on the regularity of menses. In young women, irregular menses is a more common symptom of ovarian insufficiency than permanent amenorrhea. Follicle-stimulating hormone (FSH) levels change daily, vary across cycles, and cannot be compared unless they are measured on day 2 or 3 of the menstrual cycle, which the studies failed to do. Anti-müllerian hormone (AMH) levels and antral follicle counts (AFC) are better predictors of ovarian reserve. Studies that utilized AMH and AFC did not report any benefit of GnRH agonists to improve resumption of menses or decrease amenorrhea rates [36-39]. Importantly, none of the studies are double blind or placebo controlled. When subjective criteria, such as self-reported vaginal bleeding, are used under such circumstances, risk of recollection bias is significant.
Breast cancer — Several meta-analyses reported improved rates of menstrual function in women treated with a GnRH agonist and chemotherapy compared with those receiving chemotherapy alone [40-43], while others reported no difference in menstrual function between treatment and control groups [36,44,45]. These disparate results may be explained by differences in inclusion criteria, tamoxifen use, and length of follow-up (12 month follow-up or longer) among the studies.
In a 2018 meta-analysis of 873 women that restricted inclusion criteria to premenopausal patients with early stage breast cancer who were receiving neoadjuvant chemotherapy with or without a concurrent GnRH agonist, GnRH agonist co-treatment reduced the rate of posttreatment ovarian insufficiency (14 versus 31 percent, adjusted odds ratio [OR] 0.38, 95% CI 0.26-0.57) . However, in the meta-analysis, the data were not corrected for differences in POI criteria. In addition, the meta-analysis only represented approximately one-half of all studies, predominantly the positive ones, and excluded those done in women with hematologic cancers. There is no biological rationale for focusing meta-analysis on a single cancer type. Moreover, there was no difference in the one-year amenorrhea rate, which was the only outcome measure where the data were truly individualized. Therefore, the authors believe this study does not offer sufficient evidence in favor of ovarian suppression. As discussed above, for women who desire fertility preservation, we offer established cryopreservation therapies. (See 'Fertility preservation' above.)
The complexity of study data is demonstrated by a 2015 trial done to determine if treatment with the GnRH agonist goserelin preserved ovarian function in women receiving chemotherapy for breast cancer. This trial randomly assigned 218 premenopausal women with operable, receptor-negative breast cancer to receive either standard chemotherapy or standard chemotherapy with goserelin treatment . The primary outcome of the trial was return of ovarian function, as measured by resumption of menses and FSH levels. Secondary outcomes included pregnancy rates and disease-free survival.
●Of the 135 women with complete primary endpoint data, fewer women treated with goserelin and chemotherapy had ovarian failure compared with women receiving standard chemotherapy only (8 versus 22 percent, respectively), though the confidence interval for the ORs was wide (OR 0.30, 95% CI 0.09-0.97).
●Of the 218 women who were randomly assigned, women treated with goserelin were more likely to become pregnant (21 versus 11 percent) and more likely to deliver one or more babies (15 versus 7 percent) compared with women receiving standard chemotherapy only.
●Of the women who could be evaluated for disease-free survival, the rate of disease-free survival at four years was better for the women receiving goserelin (89 versus 78 percent).
However, this study had several methodological weaknesses :
●The endpoints used in this study (eg, cessation of menses, FSH, estradiol, and inhibin-B) are poor surrogates for ovarian function and reproductive ability.
●Information on the use of assisted reproductive technology (ART) techniques in either group was not included; a difference in ART utilization could impact the pregnancy and live birth rate.
●In the study, pregnancy rates were calculated from the total study group, and there was a trend toward a higher number of women attempting pregnancy in the GnRH agonist group. However, when calculated based on the number of women trying to conceive rather than all women in the study, there is no statistically significant difference between the two groups (12/18, or 67 percent, in control versus 22/25, or 88 percent, in GnRH agonist group; p = 0.188). In addition, those who conceived were younger than those who did not; hence, it is possible that patient age, and not the GnRH agonist treatment, was the relevant variable.
●The authors did not report on the pattern of menstruation, which is significant because young perimenopausal women commonly have irregular menstruation. Without the use of placebo or blinding, women receiving the analog could interpret any bleeding as menstruation .
●Finally, the biological plausibility of this therapy is missing. Gonadotropin levels are not completely suppressed with the medication dose used in this study or when such therapy is initiated one week prior to chemotherapy, as was done in this trial . In addition, primordial follicle oocytes, which make up the ovarian reserve, do not have FSH or GnRH agonist receptors  and, hence, are not responsive to any hormonal manipulations . Gonadotoxic chemotherapy induces primordial follicle death and reduces ovarian reserve by causing severe DNA double strand breaks and activating apoptotic pathways in the human ovary, and not by follicle activation [51,52]. In an animal study, the authors demonstrated that GnRH agonist coadministration did not prevent chemotherapy-induced primordial follicle DNA damage and apoptotic death .
Other cancers — We do not offer GnRH analog co-treatment to breast cancer patients or other cancer patients undergoing cytotoxic treatment to preserve fertility or ovarian function because the results are unproven and data conflict [45,54,55]. We offer patients undergoing chemotherapy for other indications (table 2) proven cryopreservation techniques. Studies evaluating treatment with GnRH agonists and chemotherapy versus chemotherapy alone across several types of malignancies have reported similar pregnancy rates despite the addition of a GnRH agonist [45,54].
The body of evidence suggests that co-treatment with a GnRH agonist is not helpful in treating patients with other types of malignancies. However, the data conflict as to the impact of GnRH agonists and are difficult to interpret because of inconsistency in disease selection and drug regimens.
●Supporting GnRH use – Two meta-analyses reported lower rates of premature ovarian failure in women treated with a GnRH agonist and chemotherapy compared with women receiving standard chemotherapy alone, but multiple types of cancers and chemotherapy regimens were included [54,55].
●Lack of GnRH benefit – In a different, larger meta-analysis of 10 trials, women treated with a GnRH agonist and standard chemotherapy did not have improved resumption of ovarian function compared with women who did not receive a GnRH agonist (68 versus 60 percent, relative risk 1.12, 95% CI 0.99-1.27) . Sub-analyses by type of malignancy, patient age, and type of GnRH agonist found no difference in outcome with treatment. Lastly, analysis by markers of ovarian reserve, including FSH, AFC, or AMH, reported no benefit to GnRH agonist co-treatment.
Addition of a GnRH agonist to hormonal suppression (eg, norethindrone/norethisterone) has not been associated with improved ovarian function . Likewise, a recent Cochrane meta-analysis did not demonstrate any protective effect of GnRH analog coadministration during chemotherapy on pregnancy rates in women with breast cancer, ovarian cancer, and Hodgkin's lymphoma .
Heavy menstrual bleeding — We do use GnRH agonists to prevent menorrhagia in women at risk for severe chemotherapy-induced thrombocytopenia. If possible, the GnRH agonist should be initiated at least two to three weeks before chemotherapy to allow sufficient time for down regulation and to avoid any flare up-related bleeding and continued until the end of chemotherapeutic treatment. Side effects include hot flushes and vaginal dryness. (See "Management of menorrhagia during chemotherapy", section on 'Primary prevention of menorrhagia'.)
Concerns — The safety of the use of GnRH agonists in cancer patients has not been established in long-term studies. Since GnRH receptors are expressed by a variety of cancers and mediate several effects (eg, inhibition of proliferation, induction of cell-cycle arrest, and inhibition of apoptosis), it is possible that GnRH agonist therapy concomitant with chemotherapy might reduce the efficacy of the implemented chemotherapy [57,58]. However, a subsequent meta-analysis did not find a difference in survival between those who used GnRH agonists versus those who did not for gonadal preservation purposes .
Mechanism of injury — Ovarian follicles are sensitive to DNA damage from ionizing radiation. Radiation treatment induces massive DNA double strand breaks in primordial follicle oocytes and Chk2-dependent apoptotic death mechanisms . Ovarian radiation can result in the depletion of primordial follicle reserve as well as severe stromal scarring, which manifest as ovarian atrophy. The degree of ovarian damage depends on the dose of radiation delivered to the ovaries as well as the preexisting ovarian reserve, which is largely dependent on female age, and can be compounded by the addition of chemotherapy. Medical treatments to reduce radiation-induced ovarian damage have not been successful in humans [60,61].
Transposition (oophoropexy) — When a radiation field has been planned for the treatment of a cancer, the radiation oncologist and reproductive surgeon can work together to plan a surgical procedure that will move the ovary to a position out of the radiation field. In selected patients with non-pelvic tumors and a narrow midline radiation field, simple oophoropexy may be useful for preventing radiation-induced ovarian injury . In patients receiving broad pelvic radiation, transposing the ovaries out of the radiation field is an option for preserving gonadal function in the absence of chemotherapy. (See "Ovarian transposition before pelvic radiation", section on 'Patient selection'.)
Transposition can be performed laparoscopically just before the start of radiation therapy. Performing the procedure close to the time of irradiation decreases the chance of failure from ovarian migration back into the field of treatment . A combined approach can also be implemented: One ovary is cryopreserved, and the other can be transposed [63,64]. The procedure and its outcome are described separately. (See "Ovarian transposition before pelvic radiation", section on 'Procedure'.)
Reported success rates are inconsistent, varying between 16 and 90 percent . The failures are due to various factors such as scatter radiation, vascular compromise, radiation dose, the age of the patient, and whether the ovaries are shielded during the radiation procedure. Complications, such as chronic ovarian pain, infarction of the fallopian tubes, and formation of ovarian cysts have been reported during long-term follow-up [66-68]. Ovaries can also "migrate" back to their original position. (See "Ovarian transposition before pelvic radiation", section on 'Ovarian function'.)
When ovarian function is preserved, spontaneous pregnancies have occurred without repositioning the ovaries back to their original location; therefore, ovaries are not repositioned unless the patient fails to conceive. If she needs in vitro fertilization, oocyte collection from transposed ovaries may have to be performed transabdominally rather than transvaginally. Embryos generated from the oocytes retrieved from the transposed ovaries can be used for transfer into the patient, or, if she has undergone hysterectomy, they can be transferred to a gestational carrier . (See "Ovarian transposition before pelvic radiation", section on 'Pregnancy'.)
Shielding — Externally shielding the ovaries to reduce the effects of scatter radiation is an option for women with radiation fields distant from the pelvis. Similarly, gonadal shielding may be an option for males undergoing radiation, only if sperm collection is not possible. (See "Radiation-related risks of imaging", section on 'Shielding'.)
Autotransplantation — In females planning to undergo radiation therapy to the pelvis, autotransplantation of a fresh ovary to the upper extremity with creation of vascular anastomosis has been suggested to remove the ovary from the radiation field and thus protect it from radiation damage . However, the practicality of this approach is in question. Anastomotic failure can result from vascular thrombosis (due to stenotic lesions that develop because of intimal hyperplasia or endothelial damage) or shear stress produced by turbulent flow. This approach differs from cryopreservation of ovarian tissue with subsequent orthotopic or heterotopic transplantation in that the entire ovary is surgically attached to a new vascular supply without intervening with freezing .
RESOURCES FOR PATIENTS AND CLINICIANS
●Cancer.net – A website for patients by the American Society of Clinical Oncology (ASCO)
●ReproductiveFacts.org – A website for patients by the American Society for Reproductive Medicine (ASRM)
●LIVESTRONG Fertility – Provides information on treatment and eligibility for discounted rates for fertility preservation interventions
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Preserving fertility after cancer treatment in children (The Basics)" and "Patient education: Preserving fertility after cancer treatment in men (The Basics)" and "Patient education: Preserving fertility after cancer treatment in women (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Referral to discuss fertility preservation – All patients who are considering gonadotoxic therapy or gonad-removing surgery and who desire future fertility are referred to a reproductive endocrinologist for a discussion of fertility preservation options. (See 'Rapid referral for counseling' above.)
●Dual considerations for reproductive function – When considering reproductive function, clinicians must separately address the patient's desires for future fertility and potential preservation of hormone production. (See 'Assess patient goals for therapy' above.)
●Methods of fertility preservation – The most well-established method for preservation of childbearing potential in patients at risk of gonadal failure is embryo cryopreservation. When embryo cryopreservation is not feasible, alternate approaches include oocyte and spermatozoa cryopreservation. Cryopreservation of ovarian tissue is now largely considered an established fertility preservation method with increased success rates. Testicular cryopreservation is currently entirely experimental and techniques for autotransplantation have not been established. Tissue cryopreservation may be the only option of fertility preservation for prepubertal children. (See 'Cryopreservation' above.)
●Alternatives to fertility preservation –Alternate options of fertility treatment include use of donor oocytes, gestational carriers, or adoption. (See 'Other methods to preserve or restore fertility' above.)
●Unclear role of GnRH therapy – The efficacy of gonadotropin-releasing hormone (GnRH) therapy for preservation of fertility and/or ovarian function is difficult to assess because many studies have used unreliable or unsuitable surrogate outcomes. In addition, most of the studies have assessed the treatment in populations that included multiple different diseases or different stages of one disease. (See 'Limitations' above.)
•We do not recommend ovarian suppression with GnRH agonists for fertility preservation or ovarian protection as better quality data report no benefit. (See 'Our approach' above and 'Data presentation' above.)
•The safety of the use of GnRH agonists in cancer patients has not been established in long-term studies. (See 'Concerns' above.)
●Potential for ovarian transposition and shielding – For individuals with ovaries who are planning radiation therapy without chemotherapy, additional options for preservation of ovarian function include ovarian transposition out of the radiation field and radiation shielding. These approaches can be used in conjunction with established cryopreservation techniques. (See 'Radiation-sparing approaches' above.)
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