Introduction
When a pediatric or adolescent patient is planning to undergo a therapy that may affect their fertility in the future, medical organizations including the American Society of Clinical Oncology, the American Society for Reproductive Medicine, , the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics agree that offering a full range of fertility preservation treatments is the standard of care. The field of fertility preservation is still often referred to as oncofertility because many patients undergoing cancer treatment are at risk of infertility and subfertility, but fertility preservation is not just for patients with cancer. Many patients with nononcology diagnoses undergo gonadotoxic therapies, such as patients with lupus receiving multiple rounds of cyclophosphamide or those with congenital anemias undergoing hematopoietic stem cell transplants. Some patients have conditions that may predispose them to primary ovarian insufficiency (POI), such as Turner syndrome. Any patient with Turner syndrome who has achieved menarche should be considered for fertility preservation. Although the magnitude of the fertility risk is unclear, transgender male patients undergoing gender-affirming testosterone therapy are also candidates for fertility preservation. See Table 23.1 for examples of conditions that may necessitate gonadotoxic therapies. Fertility preservation options exist also for patients with testes; however, this chapter will focus on options for young patients with ovaries.
| Oncologic Conditions | Anemia | Autoimmune | Other |
|---|---|---|---|
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Patients should be fully informed about the effects that their conditions and/or recommended treatments could have on future hormonal and fertility-related outcomes. In qualitative studies, some patients describe the risk of infertility as more devastating than the cancer diagnosis itself. , 
Adolescent patients and their families value early, frequent, and matter-of-fact conversations about fertility preservation, even when options are limited.
Treatments that affect fertility
Different therapies have differing effects on the organs and processes required for fertility. Fig. 23.1 summarizes the ways that the hypothalamic-pituitary-gonadal axis and the reproductive tract can be affected.
Chemotherapy
Chemotherapy can result in ovarian insufficiency in a class- and dose-dependent manner. According to the longitudinal Childhood Cancer Survivor Study, 6% of cancer survivors experience acute ovarian insufficiency (defined as primary amenorrhea or permanent amenorrhea within 5 years of diagnosis or treatment). 
Over the longer term, 9% of cancer survivors experience POI or premature menopause. Chemotherapeutic agents, especially alkylating agents, promote follicular apoptosis, cortical fibrosis, and depletion of the follicle pool by recruitment and burnout. The resulting estrogen depletion can cause vaginal dryness and dyspareunia, affect sexual function, and decrease bone density.
Radiation
Radiation effects on fertility vary based on the location (cranial, pelvic, or total body irradiation [TBI]) and dose of treatment. Radiation to the hypothalamus or pituitary gland is associated with decreased fertility in a dose-dependent fashion, by altering release of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). 
Radiation-related deficiencies in FSH and LH can lead to hypogonadotropic hypogonadism and have effects on ovarian and sexual function. At the level of the ovaries, pelvic radiation and TBI promote follicular apoptosis and depletion of the follicle pool. Radiation to the pelvis and TBI can also result in endometrial, myometrial, and vascular damage to the uterus. This can lead to increased risk of spontaneous abortion, abnormal placentation and placental function, fetal growth restriction, fetal malposition, and premature labor. Prepubertal patients who undergo pelvic and abdominal radiation therapy can have stunted uterine growth. Finally, pelvic radiation and TBI can have deleterious effects on vaginal tissues, including fibrosis and atrophy, resulting in pain and loss of function.
Surgery
In the setting of planned pelvic surgery, the long-term fertility and endocrine effects of removal of reproductive organs should be considered and discussed with the patient. In addition to direct effects of resection of the ovaries, tubes, and/or uterus, pelvic adhesions can result in tubal factor infertility, and postoperative nerve damage can lead to sexual dysfunction by decreased arousal or inability to orgasm.
Gender-affirming care
The long-term effect of gender-affirming testosterone therapy on ovarian function remains uncertain. Ovarian stimulation after testosterone exposure is often medically feasible, but the process of stimulation and retrieval is not always desired by patients. Before testosterone treatment, discussion of fertility preservation options is beneficial, both to understand fertility preservation offerings and to consider optimal timing for an individual patient.
Clinical care pathway for fertility preservation
Assess pubertal status
The patient’s baseline pubertal status should be assessed by clinical history and physical examination (as described in Chapter 11 ).
Assess gonadotoxicity risk
Risk of gonadotoxicity is highest with certain forms of chemotherapy and with pelvic or total body radiation therapy. The risk stratification tool in Table 23.2 takes into account pubertal status, recommended therapy, and expected total dose to stratify the risk of any planned therapy into minimally increased, significantly increased, and high level of increased risk of POI. This classification system acknowledges that there is some possibility of harm with even low-risk therapies. It also recognizes that pubertal status affects POI risk. Although prepubertal status confers a protective benefit for a given dose range, it is important to note that prepubertal patients are still at risk for gonadotoxicity.
| Female level of risk for gonadal failure/infertility above that for the general population | |||||
| Minimally Increased Risk | Significantly Increased Risk | High Level or Significantly Increased Risk | |||
| Prepubertal | CED <8 | 8–12 | >12 | |
| Pubertal | CED <4 | 4–8 | >8 | ||
| Heavy metal |
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| HSCT |
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| Radiation exposure | Ovary | Prepubertal | <15 Gy | ≥15 Gy | |
| Pubertal | <10 Gy | ≥10 Gy | |||
| Hypothalamus | 22–29.9 Gy | >30–39.9 Gy | >40 Gy | ||
a CED, Cyclophosphamide equivalent dose. Calculators are available online to aid in calculating an individual patient’s CED based on the planned or prior chemotherapy regimen. For example, one may be found at: https://fertilitypreservationpittsburgh.org/fertility-resources/fertility-risk-calculator/ .
Assess medical and surgical candidacy for fertility preservation
Baseline fertility status: 
Postmenarchal patients should have baseline fertility laboratory testing, which typically includes serum FSH, LH, estradiol, and anti-müllerian hormone (AMH). These tests identify people who at baseline may already be experiencing POI from prior treatments or related to their underlying disease. AMH can predict successful oocyte cryopreservation, although it is unknown if it is able to predict future in vitro or in vivo successful use of tissue after ovarian tissue cryopreservation (OTC). Antral follicle counts (AFCs) to predict oocyte cryopreservation procedural success are typically obtained via transvaginal ultrasound, which is not recommended for prepubertal patients or for postpubertal patients who are never sexually active and/or nonconsenting.
Medical candidacy: A patient’s medical status must be considered before any fertility preservation procedure. Patients with airway limitations such as a mediastinal mass may not be safe candidates for surgical procedures. Severely cytopenic and/or immunocompromised patients may also incur higher surgical risks, which should be considered. The time frame in which the gonadotoxic therapy needs to be started also dictates the ability to do fertility preservation.
During fertility preservation treatment: If OTC is considered, minimally invasive approaches may allow chemotherapy to start the same day as the procedure; if for some reason an open surgical technique is required, this may require a longer recovery time before starting treatment. Oocyte cryopreservation results in supraphysiologic levels of estrogen, which for some patients (for example, those with sickle cell anemia) may incur additional venous thromboembolism (VTE) risks. If feasible, collaborative procedures such as combining OTC with central line placement may minimize anesthesia events for the patient and reduce costs.
After fertility preservation treatment : Significant procedural complication rates are extremely low. For OTC, complication rates are reported to be <1%. Typical pain management medications may be restricted (for example, avoiding nonsteroidal antiinflammatory drugs in a patient with thrombocytopenia), so appropriate alternative pain management modalities should be considered. Table 23.3 summarizes fertility preservation options for young patients with ovaries.
| Technique | Typical Candidates | Time Frame Required | Considerations for Pediatric/Adolescent Patients |
|---|---|---|---|
| Oocyte cryopreservation a | Postmenarchal | 2–3 weeks | Young patients may not be able to tolerate hormone self-injections, multiple (usually transvaginal) ultrasounds |
| Ovarian tissue cryopreservation | Premenarchal patients or patients of any age who either wish to avoid the process of oocyte cryopreservation or do not have the required time before gonadotoxic treatment | 1–2 days | Partial oophorectomy may be possible; because of small size of ovaries, prepubertal patients typically require whole oophorectomy |
| Ovarian shielding | Candidates planning abdominal or pelvic radiation therapy | Used during treatment | |
| Oophoropexy | Candidates planning pelvic radiation therapy | 1–2 days | More compact anatomy, may not always be feasible to move ovary out of radiation field |
| GnRH analogue therapy | Although menstrual suppression can be beneficial to reduce bleeding in the setting of chemotherapy-induced myelosuppression, GnRH analogues are NOT a proven fertility preservation method |
a Embryo cryopreservation requires a sperm partner/donor and is usually not a feasible option in young patients.
Oocyte cryopreservation
In the adolescent population, oocyte cryopreservation (OC), or egg freezing, is the fertility preservation procedure with the strongest evidence base for resulting pregnancy and live birth. In OC, injectable medications (e.g., gonadotropins) are used to hyperstimulate ovarian follicle development over about 10 to 14 days. Follicle maturation is monitored using ultrasound. This is followed by a procedure, most commonly performed under sedation, in which mature oocytes are retrieved by ultrasound-guided aspiration. The retrieved oocytes are cryopreserved using vitrification. To use the cryopreserved oocytes to achieve pregnancy in the future, the oocytes are fertilized with sperm, and embryo transfer is performed. Embryo cryopreservation, in which sperm is used to perform in vitro fertilization (IVF) immediately after oocyte retrieval to create an embryo, is not common in the adolescent population and is legally restricted in some jurisdictions. During the OC process, ultrasound monitoring and oocyte retrieval are usually performed transvaginally, although for some people a transabdominal approach may be possible. OC is available primarily to postmenarchal teens, as ovaries that have not been exposed to endogenous gonadotropin stimulation may be less likely to respond to stimulation medications. The OC process takes about 2 weeks and requires psychological readiness to undergo ovarian stimulation and the retrieval procedure; this can be difficult for very young postmenarchal patients or people with dysphoria related to gynecologic procedures or hormones. The cost of frozen oocyte storage may not be covered by insurance providers and can be a major barrier.
Ovarian tissue cryopreservation
OTC is the fertility preservation option available for premenarchal children or postmenarchal patients who do not have the time required to complete OC or cannot tolerate the procedure of OC. 
As of 2019, the American Society for Reproductive Medicine considers OTC to be an established medical procedure, no longer an experimental one. For OTC, a laparoscopic unilateral oophorectomy is performed under general anesthesia. The ovarian cortex, which contains primordial follicles, is isolated, divided into small fragments, and cryopreserved. Cryopreserved ovarian tissue can then be transplanted surgically in the future, both to achieve hormonal function and to achieve pregnancy. Ovarian tissue transplantation can be orthotopic, with fragments of ovarian cortex surgically tunneled into an existing ovary or placed in a peritoneal pocket in the ovarian fossa, or heterotopically, for example, subcutaneously in an arm. In the latter case, IVF must be performed to achieve pregnancy; however, in orthotopic transplantation (OTT), spontaneous pregnancies have been described. The live birth rate after OTC and OTT is up to 40%. , The risks of this method include the surgical risks of the oophorectomy procedure and the shorter history of this procedure. As of 2020, there have been more than 200 live births using cryopreserved ovarian tissue. The cost of tissue storage can similarly be a barrier to pursuing OTC. Although cost of the surgery itself can be prohibitive, coordination with other planned procedures (e.g., port-a-cath placement) can help to lower fees.
Ovarian transposition
Ovarian transposition (OT) is the gold standard for fertility preservation in the setting of planned pelvic radiation, for example, for cervical or rectal cancer. Using a laparoscopic approach, the ovaries are mobilized from their usual location in the pelvis and attached to the abdominal wall outside of the field of radiation. Blood supply is maintained through the infundibulopelvic ligament. Hormonal function is maintained, although depending on the transposed location of the ovaries, IVF is likely necessary for pregnancy in the future. The drawbacks of this method include the surgical risks of the transposition procedure and the risk of scattered radiation reaching the ovaries despite their transposed location.
Ovarian/pelvic shielding
During TBI, for example, in the setting of stem cell transplant, a lead shield external to the body is placed over the pelvis with a goal of protecting ovarian and uterine tissue. There is a lack of data on whether the decreased dose of TBI resulting from ovarian shielding is associated with increased relapse rate.
Pharmacologic ovarian suppression
It has been theorized that gonadotropin-releasing hormone analogues (GnRHas) administered during gonadotoxic therapies may have a protective effect on fertility by suppressing ovarian tissue at a time of high risk for rapid follicle activation and burnout. Systematic reviews of adult women undergoing chemotherapy for breast cancer showed that GnRHa co-administration increased the likelihood of having preserved ovarian function in this population, although pregnancy rates were unchanged. In other populations, data have been conflicting, and no protective fertility effect has been demonstrated. 
The 2018 American Society of Clinical Oncology (ASCO) recommendations do not support using GnRHa in place of proven fertility preservation methods. However, the menstrual suppression achieved with GnRHa can be beneficial to reduce bleeding in the setting of chemotherapy-induced myelosuppression. If other methods of fertility preservation are not feasible, administration of GnRHa can be discussed as an unproven alternative.
Family building alternatives
Fertility preservation counseling should always include a discussion of alternative methods for family building, including using donor oocytes, gestational surrogacy, partnering with someone who has children, or adoption. It should also not be assumed that every person desires to raise children.
Shared decision making
Everyone who receives therapy known to be gonadotoxic should have a documented discussion about their risks of fertility before the gonadotoxic treatment is administered, using the risk stratification protocols as discussed previously, and should be referred for fertility preservation if desired. , All available fertility preservation options should be offered. Providers who do not feel comfortable or knowledgeable enough to have these discussions should refer to a fertility-trained specialist.
Fertility conversations should be a shared decision-making discussion. Having the discussion itself, regardless of whether a patient ultimately pursues fertility preservation, has been consistently shown to be an important factor in reducing posttreatment regret. Pretriaging patients into those who should or should not have a fertility discussion, based on factors such as perceived financial status or even prognostic considerations, is ethically fraught and risks paternalism; in general, all patients who are undergoing gonadotoxic therapies should have a pretreatment fertility discussion. All options should be discussed in the framework of risks, benefits, alternatives, and indications in language that the patient and family can understand. Concerns for overwhelming the patient and family at the time of diagnosis and care planning should also be considered; it may be helpful to provide more than one counseling session, allowing for patient processing and follow-up opportunities for questions.
Monitoring after gonadotoxic treatment
Monitoring for posttreatment gonadal insufficiency is recommended in childhood cancer survivors, regardless of whether fertility preservation procedures have been performed. , Although no clear guidelines are established, a potential standardized protocol for POI surveillance has been proposed ( Table 23.4 ). Throughout monitoring, it is important to counsel patients that spontaneous pregnancy can occur. 
In the setting of POI in adolescence, there is a 5% to 10% chance of pregnancy related to spontaneous ovulation. For patients who are not planning a pregnancy, use of effective contraception is recommended.
