INTRODUCTION

More than 400,000 children (aged 0–19 years) in the world are diagnosed with cancer each year.^1,2 The most common types being leukemia, central nervous system tumors, neuroblastoma, lymphoma, and kidney tumors and bone tumors. After many advancements throughout the years, most childhood cancers can be cured with oncologic therapies, such as chemotherapy, radiotherapy, and surgery. In developed countries, the 5-year survival rate has increased to more than 80%.¹ Globally, the 5-year survival rate is 37.4% with large variation by region.³

As childhood and adolescent cancer survival rates continue to increase, there is an increased emphasis on managing the late effects related to the oncologic therapies. In particular, the gonadotoxic effect of radiation therapy and chemotherapy, reproductive outcomes, and psychosocial impact.

THE IMPACT OF ONCOLOGY THERAPY ON FEMALE REPRODUCTIVE HEALTH

Although cancer treatments such as chemotherapy and radiation are designed to cure cancer, it is also associated with long-term sequelae, including pituitary dysfunction, hypothyroidism, adrenal complications, low bone mineral density, cardiovascular disease, and infertility.⁴ More specifically, females are born with an ovarian reserve that consists of a finite number of primordial follicles. In addition to the continued and gradually accelerated decline of these follicles, oncologic therapies can be gonadotoxic and significantly reduce this reserve. Depending on the degree of loss of the ovarian reserve, this could manifest as retaining ovarian function, amenorrhea after treatment completion, or experiencing menopause before the age of 40 years. Alkylating agents, radiation directed to the abdominopelvic region or cranium, and hematopoietic stem-cell transplant are all gonadotoxic and can significantly increase the risk of premature ovarian insufficiency and associated infertility.

Chemotherapy Effects on Fertility

At birth, the ovary contains approximately 1–2 million oocytes formed as primordial follicles, which decline with age. The number of primordial follicles is a direct indicator of fertility reserve in which there is an ongoing decline with age or ovarian disruption.⁵ Chemotherapy induces toxicity on the ovaries directly by targeting actively dividing cells, thus inducing apoptosis in granulosa cells, which are supporting cells around the oocyte, and destroying mature ovarian follicles. Chemotherapeutic treatments, such as alkylating agents, platinum-based compounds, and anthracycline antibiotics, are gonadotoxic by causing DNA strand breaks and oxidative stress leading to accelerated activation, apoptosis, and inflammation of primordial follicles.⁶ Their mechanisms are also implicated causing damage to blood vessels and increased fibrosis of the ovarian cortex.^4,7,8 This mode of injury results in local ischemia leading to dysfunctional primordial follicle growth and survival.^9,10

There are short-term and long-term effects of chemotherapy drugs on the ovaries. During treatment, the drugs may acutely destroy growing ovarian follicles causing temporary amenorrhea. The long-term effect of chemotherapy may be a reduced ovarian reserve leading to infertility and/or premature ovarian insufficiency (POI). Several factors may affect the extent of ovarian damage, including age, type of drug, and dosage. Alkylating drugs (cyclophosphamide, procarbazine, busulfan, chlorambucil) are considered the most damaging chemotherapies for fertility due to their non-specific cell-cycle function.¹¹

Radiation Effects on Fertility

Radiotherapy represents a cornerstone in cancer treatment, in which several types of cancer may require radiation therapy. Radiation is an effective oncologic therapy through directly killing cancer cells or causing direct DNA damage leading to cell death. Similarly, radiation of the ovary can damage oocytes, destroy granulosa cells causing ovarian follicle loss, cause vascular damage, and increase stromal fibrosis.¹⁰ Additionally, increased fibrosis and vascular damage has also been seen in the uterus and vagina causing increased poor pregnancy outcomes or dyspareunia, respectively.

The impact of radiation on fertility also depends on several factors, including age, irradiation field, type, dose, and duration of the treatment.¹² Younger patients are more likely to maintain fertility compared to adult survivors, likely due to the larger ovarian reserve present at the time of treatment.¹¹ Due to the radiation-induced ovarian follicular atrophy and the subsequent depletion of the ovarian reserve, patients undergoing abdominopelvic radiation are at risk of accelerated reproductive aging potentially leading to the development of POI.^7,13 Ovarian dysfunction is often unpredictable with intermittent periods of function, but POI may also be permanent.^14,15

Cranial irradiation may also induce infertility by disrupting the hypothalamic-pituitary-gonadal axis with consequent disturbance of the normal hormone secretion.¹⁶ Radiation-induced dysfunction to the hypothalamus and anterior pituitary gland is dose dependent and can lead to gonadotropin deficiency.¹⁰ The pulsatile secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus is responsible for the luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion by the pituitary.^17,18 Therefore, a disruption in the gonadal axis and subsequent gonadotropin deficiencies can affect the menstrual cycle and overall fertility. The replacement of sex steroid hormones with estrogen and progesterone will be required.¹⁹ However, for women desiring pregnancy who have not had gonadotoxic therapy to the ovaries, ovulation can be induced with exogenous gonadotropins, since the egg supply was not affected.^20,21

Hematopoietic Stem-Cell Transplantation

Hematopoietic stem-cell transplant (HSCT) is a curative therapy for certain types of cancers, including leukemia and lymphoma. Before the transplant, myeloablative conditioning is often required to ensure sufficient immunosuppression and prevent rejection of the transplant. Myeloablation can be executed with regimens involving radiation, chemotherapeutic drugs, or both. The most common preparative regimen is total body irradiation or high-dose alkylating agents, which can lead to POI and infertility.^22,23 HSCT is increasingly becoming the standard-of-care for malignant and nonmalignant diseases, and with their cures comes the considerable burden of deleterious effects on the ovaries.^24,25 In addition to the increased risk of POI, another potential late effect of HSCT is graft-versus-host-disease (GVHD) to the genitals.

Risk Calculation

Infertility rates range from 11% to 26% among female childhood cancer survivors.²⁶ The toxicity that incurs from oncologic treatment is not uniform across all adolescent females and all treatment plans. In prepubescent females, radiation directed at the abdominopelvic at greater than 15 Gy incurs the greatest risk of gonadotoxicity that can lead to developing POI and even infertility. Conversely, older patients are more sensitive to gonadotoxic therapy and radiation levels greater than 10 Gy will incur the same level of risk for postpubertal patients.²⁷ Cranial radiation doses greater than 30 Gy significantly increase the level of risk.²⁸ Alkylating agent doses greater than 12 cyclophosphamide equivalent dose (CED) in prepubertal patients and greater than 8 (CED) in postpubertal patients incur the highest level of gonadotoxicity risk.²⁹ All myeloablative regimens are also associated with high levels of increased risk.^26,30

Providing an estimate of gonadotoxic risk should be included during chemoradiation treatment discussions and patients/families should be given the option of pursuing fertility preservation if desired. Interventions in preserving fertility may be costly and come with exposure to additional risks from surgery and anesthesia. Therefore, the risk of POI is important clinical knowledge to provide expectations on infertility and make decisions on the appropriate measure of fertility preservation, ultimately to provide comprehensive cancer care.³¹ It is important to note that there is very limited data on the risks associated with a number of oncologic therapies. For further information on calculating infertility risks, please refer to the gonadal insufficiency and infertility risk stratification system provided by the Pediatric Initiative Network.³⁰

FERTILITY PRESERVATION FOR ADOLESCENTS

Oncologic therapies can compromise ovarian function and future fertility of cancer survivors. Thus, fertility preservation has become an important quality-of-life factor for many survivors of adolescent cancer, and health care providers should initiate discussions during counseling prior to treatment. Ideally, fertility preservation interventions would be executed before cancer treatment, but oocyte and embryo cryopreservation can also be offered between chemotherapy cycles, after surgery but before chemotherapy, or after treatment completion if the patient has not endured permanent POI. Cancer treatment takes top priority, which can delay or interfere with the efforts of preserving fertility. Embryo and oocyte cryopreservation are standard strategies for fertility preservation only for postmenarcheal patients but require a delay in treatment of 2–5 weeks. Ovarian tissue cryopreservation (OTC) and ovarian transposition are available methods for both pre- and postmenarcheal patients and does not require a delay in cancer treatment. OTC is no longer considered an experimental procedure, as of 2019, however, there have only been two live births from ovarian tissue transplantation of previously cryopreserved tissue obtained from prepubertal/premenarcheal girls..^32,33,34 With all the available interventions and associated risks and benefits, it is important for every health care provider to consider each patient’s unique goals and concerns and come to a shared decision.

Embryo and Oocyte Cryopreservation

Embryo and oocyte cryopreservation are clinically well-established techniques and the standard of care for fertility preservation. Embryo cryopreservation requires sperm from a male partner or a donor, which opens the door to ethical, legal, and moral concerns of embryo storage if the patient dies or she and her partner separate.^35,36 Oocyte cryopreservation is a modality that allows a woman to preserve her ability to procreate with a chosen partner in the future.³⁷ It is also only available for postmenarcheal females due to their mature hypothalamic-pituitary axis and ability to respond to controlled ovarian stimulation (COS).³⁸ Although embryo and oocyte cryopreservation are ideal prior to initiating cancer treatment, it could also be offered after treatment. However, previous studies have demonstrated diminished response to ovarian stimulation after one to two courses of chemotherapy.^39,40

Embryo and oocyte cryopreservation are procedures that require COS, which take approximately 10–14 days, however, it can take up to 4–5 weeks for referral to a fertility center, coordination of medical care, or if waiting for menstrual cycle onset.⁴¹ Therefore, it is not a suitable option for fertility preservation in patients with time constraints on initiating oncologic treatment. The stimulation regimen is initiated with gonadotrophins injections to stimulate follicular growth and development. This is then followed by gonadotrophin-releasing hormone (GnRH) antagonists to prevent premature ovulation and luteinization. The conventional final step for COS was using human chorionic gonadotropin (hCG) to induce final follicular maturation. However, due to the risk hCG has shown for ovarian hyperstimulation syndrome, a rare but serious and potentially fatal complication, recent studies and clinical practice have shifted to an increased use of GnRH agonists to trigger the final follicular maturation step.^42,43,44

Follicle development is monitored throughout COS with transvaginal or transabdominal ultrasounds and blood tests for hormone levels. At the end of the stimulation regimen, matured oocytes are collected with ultrasound-guided transvaginal needle aspiration under sedation. Transabdominal needle aspiration is also an available option for younger females. Collected oocytes are subsequently isolated by stripping away cumulus cells and only mature oocytes (metaphase II) proceed with cryopreservation by vitrification. For embryo cryopreservation, the oocytes then undergo fertilization. This may be facilitated by conventional in-vitro fertilization (IVF), a method of co-incubating oocytes with sperm, or by intracytoplasmic sperm injection (ICSI), a method shown to have higher fertilization rates when compared to the conventional method.^45,46 Embryos are then incubated and grown for 5–6 days to the blastocyst stage and then cryopreserved.⁴⁷

Historically, oocytes and embryos were cryopreserved by a slow-freezing technique that takes 1–2 hours and requires expensive instrumentation equipment.^48,49 Current recommended practice involves rapid cooling, also known as vitrification, which is a procedure that takes only a few minutes, does not require specialized equipment and is more likely to avoid the formation of ice crystals in the intracellular and extracellular space.⁵⁰ Embryos are more resistant to damage caused by cryopreservation than oocytes. While in metaphase II, mature oocytes are fragile and susceptible to ice-crystal formation due to their large size, high water content, low surface to volume ratio, and presence of the meiotic spindles.^51,52 Additionally, meiotic spindle microtubules are highly sensitive to temperature deviation with transient exposures causing irreversible damage, which may result in aneuploidy after fertilization of thawed oocytes.^53,54,55,56 In previous years, slow-freezing was prone to ice-crystal formation that led to poor success rates for oocyte cryopreservation. With the continued advancements in vitrification, this rapid supercooling method has been more likely to avoid ice-crystal formation and increase post-thaw survival, fertilization, and clinical pregnancies to similar rates as fresh embryos and oocytes.^57,58,59 In the general population, oocyte cryopreservation demonstrates post-thaw survival rates that are greater than 90% and successful pregnancy rates have been reported to be as high as 50% in adult women with expectations of higher rates in adolescents.^60,61 It is important to note that the success rates are related to the number of oocytes retrieved in which underlying cancer may cause ovarian suppression leading to lower response rates. Additionally, patients with time constraints may be only allotted one attempt of COS as compared to other patients that may pursue multiple cycles to retrieve more oocytes. In embryo cryopreservation, post-thaw survival rates are varied between 82–99%, clinical pregnancy rates are between 26–60%, and live birth rates are between 15–56%.⁶² There continues to be a gap in research on fertility preservation outcomes in patients that underwent intervention in adolescence.

Ovarian Tissue Cryopreservation

Ovarian tissue cryopreservation (OTC) has recently been accepted as a standard method for fertility preservation in patients receiving gonadotoxic treatment.³² As it does not require COS, it is one of the few methods available for premenarcheal females. It is also an option for patients that cannot delay oncologic therapy to complete COS. OTC is the only fertility preservation method that has shown to restore global reproductive endocrine hormone function. However, there are concerns of reseeding malignant cells in graft ovarian tissue and the risk of relapse, especially for patients with leukemia.^63,64

In this process partial or whole ovary is obtained by minimally invasive laparoscopic surgery, ovarian cortical tissue (where the oocytes reside) is then sliced into thin cortical strips, and cryopreserved. Despite the growing popularity with vitrification of ovarian tissue, slow freezing ovarian tissue has been shown better survival results than vitrification.⁵⁹ Transplantation of ovarian cortical fragments are typically placed orthotopically (in the pelvic or peritoneal cavity), however heterotopic sites have also been attempted (in the forearm or anterior abdominal wall).⁶⁵ The most common transplantation sites are onto a remaining non-functioning ovary or within the peritoneal bursa. After auto-transplantation, ovarian endocrine function is restored in approximately 95% of cases and occurs approximately 4–6 months after reimplantation with a mean duration of 4–5 years.^20,25,26 As a newer clinically accepted fertility preservation option, pregnancy and live birth rates continue to be reported. As of 2017, there have been over 130 live births from successful pregnancies using this method.³⁸ However, there have been only two successful live births from tissue that was cryopreserved from prepubertal/premenarcheal patients.^36,65

In-vitro maturation (IVM) of aspirated oocytes is an extension of both COS with oocyte cryopreservation as well as OTC, which may be an additional form of protecting fertility. This method cultures immature oocytes (germinal vesicle or metaphase I) to a mature state (metaphase II) required for fertilization. IVM is still in its infancy and recently is no longer considered experimental but may be a feasible option for cryopreserving mature oocytes in the premenarcheal patient population.⁶⁶ In OTC, it is an option that can be done before the tissue is cryopreserved or after the tissue is thawed.^67,68,69 IVM of aspirated oocytes also serves as a safer option for patients at risk of possible malignancy reseeding.⁷⁰ OTC has also been performed after complete remission and has shown a decrease in risk of seeding.⁷¹ Previous studies have shown no significant difference between pre- and postmenarcheal patients in the number of aspirated oocytes. However, the overall IVM rate was significantly higher in the postmenarcheal group.⁷² Additionally, very young females (less than 6 years) have substantially decreased IVM rates making this an invaluable option for this age group.⁷³ To our knowledge, there have been six live births following the use of OTC and IVM of immature oocytes from ovarian tissue collected from adult women.^74,75,76,77 However, clinical data on OTC-IVM outcomes is very limited and scarce, thus this method continues to be experimental.

In postmenarcheal patients, combining OTC with COS and subsequent oocyte/embryo cryopreservation is an innovative technique that can be used to maximize efficiency of preserving fertility. In these cases, OTC could be performed prior to starting COS to avoid cryopreserving tissue from expanded ovarian cortex or bleeding corpora lutea, after as a backup method if the ovary does not respond well to COS with few oocytes retrieved, or after chemoradiation is complete and in remission if spontaneous menses resumes.^78,79 Tissue harvesting has been shown to not affect the number or quality of the collected matured oocytes after COS.⁸⁰

Ovarian Transposition

Ovarian transposition, also known as oophorepexy, is the first procedure in history proposed to preserve fertility in females with cancer.⁸¹ The method is indicated in patients requiring abdominopelvic radiation as part of their oncologic treatment. This surgical procedure includes repositioning one or both ovaries out of the direct field of radiation. It is generally performed after neoadjuvant chemotherapy. The procedure may be a minimally invasive surgery on its own or performed during the resection of an abdominal or pelvic tumor. The procedure is associated with adverse effects such as ovarian torsion, adhesion formation, and ovarian cysts.^82,83 Additionally, OTC could be performed concomitantly with the ovarian transposition procedure to increase the opportunity for future fertility. Ovarian endocrine function has been preserved relatively efficiently with ovarian transposition in approximately 60% of patients. However, only 15% of patients treated with transposition and desire conception are able to achieve pregnancy, though this is based on relatively low numbers of reported patients.⁸⁴ Additionally, the long-term effects of ovarian transposition on adolescents have not been well studied.

Gonadal Protection

GnRH agonists have been considered to provide pharmacologic protection of the ovary during chemotherapy. It is thought to induce hypogonadotropism ovarian quiescence as well as reduce ovarian blood flow.⁸⁵ Recent studies in adult women with breast cancer and lymphoma have shown contradictory evidence regarding the effectiveness of GnRH agonists in preventing premature ovarian insufficiency. The use of GnRH agonists exclusively for fertility protection remains controversial with clinical evidence remaining uncertain of the effects on ovarian function and should not be the first-line option for fertility preservation over oocyte cryopreservation or OTC.⁸⁶

REPRODUCTIVE HEALTH MANAGEMENT FOR ONCOLOGIC THERAPY

Menstrual Suppression

Patients undergoing oncologic therapy are at risk of heavy menstrual bleeding (HMB) from treatment-induced myelosuppression leading to thrombocytopenia.⁸⁷ Menstrual blood loss can threaten a patient who may already be affected by anemic, thrombocytopenic, or both potentially leading interventions, such as blood and platelet transfusion. HMB can affect health-related quality of life as well as be troublesome in an already stressful situation. To avoid the risk of HMB, the menstrual cycle can be temporarily suppressed with various medical treatments. Options for menstrual management include combined hormonal contraceptives, progestin-only therapy, GnRH agonists, and progestin-containing intrauterine devices (IUDs). Each option has different mechanisms of action and side-effect profiles. Therefore, it is appropriate to take into consideration the patient’s current menstrual status, hemoglobin and platelet counts, planned treatment regimen, risk of venous thromboembolism (VTE), and contraception goals.

GnRH agonists can be used to interrupt the hypothalamic-pituitary-gonadal axis and suppress the menstrual cycle.⁸⁸ It has been demonstrated to be the most effective method for menstrual suppression with rates as high as 96%.^89,90 GnRH agonists typically induce a transient increase in gonadotropins and estrogen, potentially leading to increased bleeding in the first 2–4 weeks on therapy with the initial dose.⁹¹ To avoid the risk of HMB, menstrual suppression with GnRH agonists is initiated approximately ≥2 weeks before the anticipated hemoglobin and platelet nadir from oncologic treatment.⁹² Leuprolide acetate (LA) is a frequently used GnRH agonist that produces very high rates of amenorrhea in patients. The most preferred method of administration is an intramuscular (IM) dose of 11.5 mg LA every 3 months.⁸⁶ It is also available as subcutaneous or intravascular formulations. It may also be given as IM doses of 3.75 mg every month or 45 mg IM every 6 months. It is recommended to continue throughout cancer treatment until 3 months after chemotherapy is complete. GnRH agonists are also a popular option due to the potential ability to confer some fertility preservation benefit, although this is controversial and there is no clear consensus on this. It is important to note that GnRH agonists are not considered contraception. Therefore, if GnRH agonists are used for menstrual suppression, health care providers should assess a patient’s need for a contraceptive method.⁹³

With the suppression of the menstrual cycle, patient may begin to experience menopausal symptoms including mood changes and vasomotor symptoms. This may be uncomfortable or even intolerable especially for young patients. Additionally, suppression of estrogen may also cause decreased bone mineral density. Adolescence is a particularly critical period for bone accrual. Therefore, hormonal add-back therapy should be strongly considered to mitigate these effects. Norethindrone acetate 5 mg orally daily is commonly used for add-back therapy and has been shown to protect bone health and prevent menopausal symptoms.^94,95 It has also been used alone as a method of menstrual suppression. It must be noted that norethindrone acetate does have estrogen effects and may be associated with an increased risk of VTE.^96,97

Other options for menstrual suppression include progestin-only therapy, such as progestin-only pills, depot medroxyprogesterone acetate (DMPA) IM injections, etonogestrel implant, and levonorgestrel IUDs. Progestin-only oral therapy includes medroxyprogesterone acetate (10–20 mg/day), norethindrone acetate (5–10 mg/day), norethindrone (0.35 mg/day), or drospirenone (4 mg/day). Medroxyprogesterone acetate is recommended for chronic and acute bleeding control, while norethindrone acetate is effective for acute bleeding control.^98,99 Norethindrone and drospirenone do not produce the same control as other oral progestins but have been shown to have contraceptive action and have fewer side effects.^100,101 Depot medroxyprogesterone acetate, etonogestral implant, and levonorgestrel IUDs all provide adequate contraception but do not deliver the same degree of amenorrhea when compared to GnRH agonists.^102,103,104

When used consistently, combined hormonal contraceptives can effectively achieve amenorrhea.^105,106 However, combined hormonal contraceptives are contraindicated in patients with active malignancy (metastatic, receiving therapy, or within 6 months after clinical remission) due to increased risk of VTE with estrogen use.¹⁰⁷ Copper IUDs are known to cause abnormal uterine bleeding and are not considered for menstrual suppression, thus are not recommended.

Conditioning regimens and HSCT can also cause thrombocytopenia. In this special patient population, the use of intrauterine foreign bodies during neutropenia or active immunosuppression may be associated with increased likelihood of infections. However, no studies have provided data regarding the safety of IUDs.¹⁰⁸ If a patient is already amenorrheic with a progestin-containing IUD prior to the conditioning regimen, health care providers must counsel the patient on the risks associated with continued IUD use while undergoing HSCT and decide together whether to keep it in place or remove it prior to transplant. Due to unpredictable bleeding post-insertion of IUDs and implants, these methods are not recommended for initiation as part of the transplant care.¹⁰⁹

Preventative Reproductive Health

Many patients are unaware of their fertility status while on oncologic therapies. This may lead to patients underestimating their risk of pregnancy and engaging in riskier behaviors.¹¹⁰ Cancer treatments are also known to pose teratogenic risks to a fetus.¹¹¹ Therefore, health care providers should assess the patient’s risk of pregnancy and discuss contraceptives needs, expectations, and concerns. Selection of a contraception method should consider the contraindications associated with cancer, including the innate hypercoagulability of cancer, in avoidance of estrogen or combined oral contraceptives.¹¹² Two absolute contraindications are the use of hormonal contraceptive methods in patients with hormonally active breast cancers and IUD insertion in patients with cervical or endometrial cancer with concerns of seeding.¹¹³ Considerations should also be made about oral contraceptives and the associated nausea and vomiting from cancer or treatments as well as poor absorption or tolerance from mucositis or diarrhea.^114,115 Due to the variety of available contraceptive methods, reproductive goals, and personal preferences of patients, discussions must be flexible to address individual needs and preferences of each patient. Patients need counseling not only on the proper and consistent use of contraceptives but also on protection from sexually transmitted infections by using barrier contraceptives.¹¹⁶

Conversations about fertility preservation may lead patients to develop incorrect beliefs about their fertility after treatment is completed.¹¹⁷ Additionally, patients experiencing amenorrhea or POI may continue to ovulate and with a 5–10% chance of conceiving spontaneously, even if the diagnosis has been established.^118,119 Therefore, contraception discussions should continue to occur post-treatment into the patient’s cancer continuum. A patient’s reproductive goals during survivorship may differ from their initial goals.

REPRODUCTIVE OUTCOMES IN FEMALE SURVIVORS OF ADOLESCENT CANCER

Premature Ovarian Insufficiency

Oncological therapies may cause an increase of risk of either temporary or permanent ovarian dysfunction leading to loss of hormonal endocrine function. Premature ovarian insufficiency (POI) can occur through ovarian follicle dysfunction or depletion, in which chemotherapy and radiation affect both.^120,121 Therefore, POI in cancer patients and survivors may manifest in multiple ways including transient “acute ovarian failure” during or after the completion of cancer treatment or experience menopause before the age of 40 years.¹²² Survivors who menstruate may continue to have an increased lifetime risk of POI, and those who experience POI after treatment may have the possibility of intermittent resumption of ovarian function.¹²³ Both subsets may lead to early and often unexpected infertility.¹¹⁹ Estrogen deprivation may also result in menopausal symptoms, such as vaginal dryness and vasomotor symptoms, as well as lead to adverse health outcomes including osteoporosis, increased risk of cardiovascular diseases, and psychosexual dysfunction.^{124,125,126,127,128}

Survivors who are at risk for ovarian dysfunction will benefit from long-term surveillance and screening for POI.¹²⁹ Early detection allows for timely management that may preserve health and quality of life.¹³⁰ There are no clear guidelines on diagnosing POI. However, commonly used parameters include amenorrhea for greater than 4 months, loss of ovarian function at ages less than 40 years, and follicle stimulating hormone greater than 25 IU/I measured twice at least one month apart.^131,132 For adolescents, POI symptoms can be particularly distressing during a time of significant developmental changes. Special considerations are required when developing an optimal treatment plan for these patients that factor in both the physical and emotional needs during their development.

Treatment for adolescents with POI involve medications to replace hormone levels. Beyond the benefits of supporting bone and cardiovascular health, hormone replacement can alleviate distressing symptoms, such as vaginal dryness and vasomotor symptoms.^133,134 To mimic normal ovarian functioning levels of estradiol, treatment can include transdermal estradiol patch 0.1 mg/day, oral 17 beta estradiol 1–2 mg/day, or oral conjugated equine estrogen 0.625–1.25 mg/day. Transvaginal estradiol can also be used for local symptoms. In adolescents who are prepubertal or peripubertal, estrogen levels can be titrated up to this adult dose to parallel gradual pubertal changes.¹⁴ There is an increased risk of VTE when using oral estrogens in comparison to transdermal estrogen due to the first pass effect and transdermal is the recommended route of administration.^135,136 To prevent endometrial hyperplasia and abnormal bleeding, progesterone can be administered continuously or cyclically for 10–12 days a month.^137,138 It is important to note that for systemic benefits, patients with POI should be given an estrogen continuously even during progestin administration. Progesterone is available as combined oral contraceptive pills, medroxyprogesterone tablets, injectables, implants, and intrauterine devices. Some combined oral contraceptives (COC) may contain higher doses of estrogen than what is preferred for hormone replacement therapy and are not recommended as first-line treatment. However, oral contraceptives are the most commonly used method of contraception in the adolescent population.¹³⁹ Therefore, COCs should be used on a continuous regimen to ensure adequate hormone replacement may be preferred by the adolescent.¹⁴⁰ Ultimately, the best hormone replacement therapy is the one that the patient is compliant with and thus as with contraception counseling careful examination of the patient’s preferences is important. In addition to estrogen therapy patients will benefit from adequate intake of calcium and vitamin D to preserve bone density.¹⁴¹

Pregnancy Outcomes

Oncologic therapies are associated with adverse reproductive health, including pregnancy rates and pregnancy outcomes. When compared to siblings, cancer survivors took significantly longer to achieve pregnancy than their siblings.¹⁴² Of the female cancer survivors, those with leukemia, breast, or cervical cancer have the lowest success rate in achieving post cancer pregnancy.¹⁴³ Oncologic therapies have also been shown to increase the risk of developing adverse pregnancy outcomes, including increased prevalence of preterm birth, low birth weight, and cesarean delivery.¹⁴⁴ Radiation may induce damage to the elastic properties of the uterus resulting in increased fibrosis that can negatively affect the uterine vasculature and volume. This results in restricted growth and blood flow to a fetus leading to preterm birth, low birth weight, and cesarean delivery.^145,146 Chemotherapy has also been associated with increased risk of preterm birth and low birth weight with unknown underlying pathophysiology.¹⁴⁷ An increase in fetal loss has been reported among Wilms tumor survivors that underwent high-dose abdominal irradiation.^148,149 However, there is no evidence of increased rates of fetal loss in patients with other types of cancers.¹⁵⁰ There is also no evidence of increase in frequency of congenital anomalies in the offspring of cancer survivors.¹⁵¹ Other less commonly reported adverse pregnancy outcomes include fetal malposition, abnormal placentation, postpartum hemorrhage, and uterine rupture.^{152,153,154,155}

Genital Graft Versus Host Disease

GVHD is an adverse outcome of HSCT mediated by donor T-cells reacting against proteins found in the recipient. GVHD can manifest as a syndrome involving clinical features of the skin, eyes, mouth, lungs, liver, or gastrointestinal tract that typically arise after immunosuppression is withdrawn.¹⁵⁶ Genital GVHD is a common but underreported complication that typically manifests 7–10 months after HSCT but can also develop late, over a year after transplant.^157,158 Prevalence is higher in recipients of mobilized peripheral blood transplants compared to bone marrow transplants.¹⁵⁹ Most patients with genital GVHD have concurrent involvement in other organs, but the severity does not necessarily correlate. In females, genital GVHD typically manifests as vulvar erythema, tender vestibular gland openings, or mucosal erosions and fissures. However, diagnostic signs include lichen planus-like features, vaginal scarring or stenosis, and vaginal adhesions. The most severe complication includes complete vaginal stenosis resulting in blood accumulating after the obstruction.

Management of genital GVHD includes routine questions about sexual health and urinary symptoms to identify early signs. The genital area should be cleaned with warm water while avoiding mechanical and chemical irritants, such as soap or feminine hygiene products. Emollients may be used on the external genitalia to provide relief from itching or irritation. Vaginal lubricants or cream may be used in the vagina for comfort. Signs and symptoms of genital GVHD are primarily treated with topical immunosuppressives. High potency corticosteroids such as clobetasol or triamcinolone ointments may be applied on the vulva once daily for 4–6 weeks. Hydrocortisone acetate foam can be applied to the vaginal daily for 4–6 weeks, followed by tapering doses. To prevent further atrophy or superinfection with Candida, the steroids can be reduced to a maintenance dose of 2–3 times a week. Mechanical interventions with vaginal self-examinations, regular vaginal intercourse, or vaginal dilators can be used to prevent or treat scarring and stenosis. The addition or standalone treatment of topical calcineurin ointments has also been used with success.^160,161 In those with low estrogen states, the physical exam findings may present similar to hypoestrogenic vaginal atrophy and can be treated with topical estrogen therapy with or without the use of a vaginal dilator.¹⁶² Severe vaginal stenosis or scarring, dense vaginal adhesions, or labial fusion can be treated by surgical efforts.¹⁶³

UNIQUE CONSIDERATIONS FOR ADOLESCENT SURVIVORS

With advancements in cancer treatment, more survivors are facing the consequence of exposure to intensive multimodal therapies. Adolescence is a period of rapid physical and developmental change. It is also a challenging and dynamic phase of life marked by career plans, romantic relationships, and gaining independence.¹⁶⁴ For many adolescent patients, the cancer diagnosis, treatment, and long-term effects of therapy can significantly affect the patient’s physical, psychological, and social well-being.^165,166 Being diagnosed with cancer and undergoing treatment regimens may lead to delays in achieving important milestones, including interacting with potential romantic partners, and forming intimate and sexual relationships.^167,168 These patients have an elevated risk of depression and anxiety when compared to adult cancer patients.^169,170 After intensive treatment, female adolescent survivors are more likely to face low self-esteem, body image issues, and anxiety regarding sexual activity.¹⁵⁰ Sexual desire and satisfaction have also been shown to be compromised in cancer survivors.¹⁷¹ For them, cancer extends into and compromises their adult life.

The long-term impact of gonadotoxic treatments may also impact sexuality. Some patients are at an increased risk of experiencing early and unexpected infertility, which has notable negative effects on marriages, sexual satisfaction, and overall psychosocial well-being.^172,173,174 The physiological effects of chemotherapy may disrupt sexual function by affecting ovarian hormones, including estrogen.¹⁷⁵ This may lead to early menopausal symptoms, including vaginal dryness, loss of elasticity, and decreasing sexual interest.¹⁷⁶ Treatment with estrogen can be used to mitigate some symptoms. Radiation has also been associated with changes in sexual sensitivity in females.¹⁷⁷

It is important for health care providers to initiate the discussion about sexual health problems during and after treatment. Providers should be comfortable and knowledgeable enough to address all sexual health concerns and confer expectations. This may include a multidisciplinary team of the oncologist and the survivorship providers, including adolescent medicine, pediatric and adolescent gynecology, reproductive endocrinology infertility, and urology.¹⁷⁸ There is also a strong need to provide resources and guidance that caters specifically to this patient population in addition to interventions to support sexual health and psychosexual adjustment.¹⁷⁹ Improved symptom control will also improve the quality of life for young cancer survivors.

Shared-Decision Making

Young females generally desire to participate in health care decisions and wish to be well-informed regardless of whether they are the primary decision-maker. These patients also tend to rely on their parents to interpret and process information regarding serious health issues.¹⁸⁰ Accordingly, it is appropriate for providers to have discussions using developmentally appropriate language, address both the patient’s and parents’ concerns and expectations, and include the patient in the decision-making process. In some nations, there are protective laws guaranteeing confidentiality for adolescents seeking and receiving health care. This allows increased access to health care services without requiring parental consent for certain medical care. In the United States, adolescent confidentiality is supported by case law and federal statutes. However, confidentiality laws vary from nation to nation, and health care providers should be familiar with their laws regarding adolescent confidentiality. Ethics may be a concern in the event of a parent’s right for decision making, a child’s decisional capacity and right to assent are at odds.¹⁸¹ It is then important to understand the factors that may contribute to the patient's and parents' health care decisions, including morals, values, and overall understanding.

PRACTICE RECOMMENDATIONS