Reproductive late effects after hematopoietic stem cell transplant in pediatric, adolescent, and young adult cancer survivors.

Reproductive late effects after hematopoietic stem cell transplant can have a significant impact on cancer survivors' quality of life. Potential late effects include gonadal insufficiency, genital graft-versus-host disease, uterine injury, psychosexual dysfunction, and an increased risk of breast and cervical cancer in patients treated with total body irradiation. Despite guidelines, screening and treatment are not standardized among at-risk patients. Provider barriers include lack of knowledge of at-risk therapies and evidenced-based guidelines. Patient barriers include a reluctance to report symptoms and lack of awareness of treatment options. System barriers include inefficient implementation of screening tools and poor dissemination of guidelines to providers who serve as the medical home for survivors. This review guides the clinician in identifying and managing reproductive late effects after hematopoietic stem cell transplant to improve outcomes.

Male pediatric, adolescent, and young adult reproductive survivorship.

As pediatric, adolescent, and young adult cancer survival rates increase, emphasis is placed on reducing late effects, including reproductive complications and potential impact to fertility. Male survivors are at risk of abnormalities in sperm, hormone deficiencies, and sexual dysfunction. This can impact one's progression into puberty and ability to have a biological child and impacts quality of life following treatment. Access to reproductive care is important and requires patient assessment and appropriate referral to reproductive specialists. This review addresses reproductive complications associated with therapy, standard-of-care testing, and therapeutic interventions. The psychologic impact on psychosexual functioning is also addressed.

Female reproductive health in pediatric, adolescent, and young adult cancer survivors.

An estimated 500,000 cancer survivors of reproductive age in the United States will live to experience the long-term consequences of cancer treatment. Therefore, a focused aspect of cancer care has appropriately shifted to include quality of life in survivorship. Infertility is a late effect of therapy that affects 12% of female survivors of childhood cancer receiving any cancer treatment in large cohort studies and results in a 40% decreased likelihood of pregnancy in young adults of ages 18-39 years. Nonfertility gynecologic late effects such as hypoestrogenism, radiation-induced uterine and vaginal injury, genital graft-versus-host disease after hematopoietic stem cell transplant, and sexual dysfunction also significantly affect quality of life in survivorship but are underdiagnosed and require consideration. Several articles in the special edition "Reproductive Health in Adolescent and Young Adult Cancer Survivorship" address infertility, genital graft-versus-host disease, and psychosexual functioning in survivorship. This review article focuses on other adverse gynecologic outcomes of cancer therapies including hypogonadism and hormone replacement therapy, radiation-induced uterovaginal injury, vaccination and contraception, breast and cervical cancer screening, and pregnancy considerations in survivorship.

Pediatric, adolescent, and young adult breast and reproductive tumors.

Tumors of the breast and reproductive organs that occur in children, adolescents, and young adults (AYA) have different biological features and can present special challenges. Although prognosis for these tumors is generally favorable, the long-term effects of treatment can be debilitating. Treatments are often multimodal and may include surgery as well as chemotherapy and/or radiation, which can cause considerable distress and anxiety related to loss of femininity or masculinity, concern over future fertility, or sexual dysfunction. Thus, tumors of the reproductive organs in pediatric/AYA patients require special consideration of the treatment effects beyond the intended oncologic outcome. Multidisciplinary teams should be involved in their care and address issues of fertility, sexual dysfunction, and psychosexual concerns before treatment begins. This review addresses histology, risk factors, prognosis, staging and treatment of gynecologic, breast and testicular cancers in pediatric and AYA patients.

Patient preferences and adherence to adjuvant GnRH analogs among premenopausal women with hormone receptor positive breast cancer.

PURPOSE: Adjuvant ovarian function suppression (OFS) in premenopausal hormone receptor (HR) positive breast cancer (BC) improves survival. Adherence to adjuvant gonadotropin-releasing hormone analogs (GnRHa) remains a challenge and is associated with toxicities and inconvenient parenteral administration. The goal of this study was to describe real-world adherence patterns and patient preferences surrounding adjuvant GnRHa. METHODS: We analyzed the medical records of premenopausal women with non-metastatic HR positive BC from January 2000 to December 2017; participants received adjuvant monthly goserelin or leuprolide at The Ohio State University. Data collected included demographics, clinicopathologic characteristics, and OFS adherence/side effects. We defined non-adherence as discontinuation of GnRHa within 3 years for a reason other than switching to an alternate OFS, delay > 7 days from a dose, or a missed dose. Chi-square tests assessed associations between clinical characteristics and outcomes. RESULTS: A total of 325 patients met eligibility. Of these, 119 (37%) patients were non-adherent to GnRHa; 137 (42%) underwent elective bilateral salpingo-oophorectomy after initial GnRHa. Those opting for surgery reported significantly more hot flashes (74% vs 48%, p < 0.001), arthralgias (46% vs 30%, p = 0.003), and vaginal dryness (37% vs 21%, p = 0.001) compared with patients remaining on GnRHa. CONCLUSION: Non-adherence to adjuvant GnRHa occurred in over a third of patients and almost half the patients initiating GnRHa underwent subsequent surgical ablation. These high frequencies highlight real-world patterns of OFS. Additionally, treatment toxicities may impact personal preference of OFS modality. Personalized practices to target predictors of adjuvant GnRHa non-adherence are critical to optimize symptoms, adherence, and survivorship.

Integrated stress response control of granulosa cell translation and proliferation during normal ovarian follicle development.

Mechanisms that directly control mammalian ovarian primordial follicle (PF) growth activation and the selection of individual follicles for survival are largely unknown. Follicle cells produce factors that can act as potent inducers of cellular stress during normal function. Consistent with this, we show here that normal, untreated ovarian cells, including pre-granulosa cells of dormant PFs, express phenotype and protein markers of the activated integrated stress response (ISR), including stress-specific protein translation (phospho-Serine 51 eukaryotic initiation factor 2α; P-EIF2α), active DNA damage checkpoints, and cell-cycle arrest. We further demonstrate that mRNAs upregulated in primary (growing) follicles versus arrested PFs mostly include stress-responsive upstream open reading frames (uORFs). Treatment of a granulosa cell (GC) line with the PF growth trigger tumor necrosis factor alpha results in the upregulation of a 'stress-dependent' translation profile. This includes further elevated P-eIF2α and a shift of uORF-containing mRNAs to polysomes. Because the active ISR corresponds to slow follicle growth and PF arrest, we propose that repair and abrogation of ISR checkpoints (e.g. checkpoint recovery) drives the GC cell cycle and PF growth activation (PFGA). If cellular stress is elevated beyond a threshold(s) or, if damage occurs that cannot be repaired, cell and follicle death ensue, consistent with physiological atresia. These data suggest an intrinsic quality control mechanism for immature and growing follicles, where PFGA and subsequent follicle growth and survival depend causally upon ISR resolution, including DNA repair and thus the proof of genomic integrity.

Ovarian stimulation for fertility preservation in an oncology patient with etonogestrel implant in place.

PURPOSE: To describe a case of a young woman who presented for fertility preservation and underwent ovarian stimulation with an etonogestrel implant in place. METHODS: A 24-year old, gravida 0, with an etonogestrel implant and newly diagnosed lower extremity sarcoma and DVT desiring oocyte cryopreservation prior to adjuvant chemotherapy and radiation. To avoid delay in her oncologic care and allow for continued use of contraception post-retrieval, the patient underwent controlled ovarian hyperstimulation (COH) without removal of the etonogestrel implant. RESULTS: Baseline labs included follicle-stimulating hormone 9 mIU/mL, luteinizing hormone 4.9 mIU/mL, estradiol 42 pg/mL, anti-Müllerian hormone 5.1 ng/mL, and antral follicle count greater than 40. The patient was placed on an antagonist protocol and stimulated with 125 IU Gonal-F and 75 IU Menopur. She received a total of 12 days of gonadotropin stimulation. On the day of trigger, her estradiol was 1472 pg/mL, lead follicle 21.5 mm with a total of 25 follicles measured > 12 mm. She was triggered with 5000 U hCG. She had a total of 23 oocytes retrieved, 17 of which were metaphase II and vitrified. CONCLUSIONS: COH and successful oocyte cryopreservation can be achieved in patients with an etonogestrel implant in situ without apparent detrimental effects to oocyte yield or maturity. Due to the etonogestrel implant's inhibitory effects on LH, it is recommended to use an hCG trigger for final oocyte maturation.

A View from the past into our collective future: the oncofertility consortium vision statement.

PURPOSE: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. METHODS: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. RESULTS: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. CONCLUSION: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Fertility Preservation for Adolescents Receiving Cancer Therapies.

According to the National Cancer Institute, ∼300,000 children globally are diagnosed with cancer each year. Advancements in chemotherapy and radiotherapy have revolutionized cancer treatment and improved long-term survival. Although many survivors will remain in good health with disease-free prognoses, three fourths will experience short-term and long-term effects from treatment. The cancer care paradigm has now appropriately shifted to include quality of life in survivorship with fertility cited as one of the most important quality of life indicators by survivors. A comprehensive approach to fertility preservation in adolescents receiving cancer therapies is described in this chapter.

The Development of an International Oncofertility Competency Framework: A Model to Increase Oncofertility Implementation.

BACKGROUND: Despite international evidence about fertility preservation (FP), several barriers still prevent the implementation of equitable FP practice. Currently, oncofertility competencies do not exist. The aim of this study was to develop an oncofertility competency framework that defines the key components of oncofertility care, develops a model for prioritizing service development, and defines the roles that health care professionals (HCPs) play. MATERIALS AND METHOD: A quantitative modified Delphi methodology was used to conduct two rounds of an electronic survey, querying and synthesizing opinions about statements regarding oncofertility care with HCPs and patient and family advocacy groups (PFAs) from 16 countries (12 high and 4 middle income). Statements included the roles of HCPs and priorities for service development care across ten domains (communication, oncofertility decision aids, age-appropriate care, referral pathways, documentation, oncofertility training, reproductive survivorship care and fertility-related psychosocial support, supportive care, and ethical frameworks) that represent 33 different elements of care. RESULTS: The first questionnaire was completed by 457 participants (332 HCPs and 125 PFAs). One hundred and thirty-eight participants completed the second questionnaire (122 HCPs and 16 PFAs). Consensus was agreed on 108 oncofertility competencies and the roles HCPs should play in oncofertility care. A three-tier service development model is proposed, with gradual implementation of different components of care. A total of 92.8% of the 108 agreed competencies also had agreement between high and middle income participants. CONCLUSION: FP guidelines establish best practice but do not consider the skills and requirements to implement these guidelines. The competency framework gives HCPs and services a structure for the training of HCPs and implementation of care, as well as defining a model for prioritizing oncofertility service development. IMPLICATIONS FOR PRACTICE: Despite international evidence about fertility preservation (FP), several barriers still prevent the implementation of equitable FP practice. The competency framework gives 108 competencies that will allow health care professionals (HCPs) and services a structure for the development of oncofertility care, as well as define the role HCPs play to provide care and support. The framework also proposes a three-tier oncofertility service development model which prioritizes the development of components of oncofertility care into essential, enhanced, and expert services, giving clear recommendations for service development. The competency framework will enhance the implementation of FP guidelines, improving the equitable access to medical and psychological oncofertility care.

The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

The Effect of Hormonal Contraception Use on Ovarian Reserve Markers and the Uptake of Assisted Reproductive Technology in Individuals Seeking an Infertility Evaluation.

Background and objective The effects of hormonal contraception (HC) use on ovarian reserve (OR) markers in individuals seeking an infertility evaluation and the success of assisted reproductive technology (ART) warrant further investigation. Therefore, the aim of this study was to determine if women seeking an evaluation for unexplained infertility who used long-term (≥2 years) HC have lower ovarian reserve (OR) markers and higher uptake of ART compared to short-term (<2 years) or never HC users. Methods We performed a cross-sectional patient survey involving a retrospective medical chart review of patients seeking an evaluation for unexplained infertility at the University of Colorado Advanced Reproductive Medicine (CU ARM) clinic. Results Most participants (87%; 107/123) reported a history of HC use with 98 (79.7%) reporting long-term continuous use for two or more years. Median OR markers were similar between long-term and short-term/never HC users [anti-Müllerian hormone (AMH): 2.4 vs. 3.2, p=0.20; antral follicle count (AFC): 18 vs. 26, p=0.10; follicle-stimulating hormone (FSH): 7.6 vs. 6.3, p=0.26] and remained so after adjusting for age and diagnosis of polycystic ovarian syndrome (PCOS) or primary ovarian insufficiency (POI) in linear regression models. However, among HC users aged less than 30 years (n=9), those who had discontinued HC between two and three years prior to the assessment of their OR markers had a 6.20 ng/mL increase in AMH level compared to those who had discontinued HC less than two years prior to the assessment (p=0.02). Additionally, there was a marginally increased use of ART overall among long-term HC users compared to short-term/never HC users (64.3% vs. 44.0%, p=0.06), specifically in the use of in vitro fertilization (IVF) (58.7% vs. 18.2%, p=0.01). Among long-term HC users, ovulation induction was less likely to result in live birth compared to short-term/never HC users (8.9% vs. 62.5%, p<0.001); however, after adjusting for age, PCOS, POI, and type of ART used, there was no difference in the odds of live birth after ART between long-term HC users and short-term/never users. Conclusion While long-term HC users report increased use of ART, in particular IVF, the overall conception rates and live birth outcomes among ART users do not appear to be significantly affected by a history of long-term HC use.

What Does Dobbs v. Jackson Mean for Oncology Patients and Providers? Current Considerations for Pregnancy and Fertility in the Oncology Setting.

The incidence of cancers such as colorectal cancer, head and neck cancer, and melanoma has increased in younger patients. The number of cancer survivors is also increasing in the US. Pairing these facts together, there are many people with cancer for whom pregnancy and fertility concerns are crucial aspects of their oncologic and survivorship care. For these patients, understanding and having access to fertility preservation options is an essential part of their care. At JADPRO Live 2022, a panel of experts from diverse professions provided perspectives on the consequences for the treatment landscape after the Dobbs v. Jackson decision.

Reproductive and Family Building Considerations for Female Patients with Anorectal And Urogenital Malformations.

BACKGROUND: Little is known about fertility and pregnancy outcomes in patients with anorectal malformations (ARM), particularly those with long common channel cloaca and cloacal exstrophy who may have impaired fertility. The purpose of this study is to describe pregnancy and offspring data from a cohort of patients with ARM. METHODS: A retrospective review of female patients with ARM from our database, which includes patients operated on since 1980, was performed as well as a review of the literature. Demographic, operative, and self-reported fertility, obstetric, and offspring data were collected. RESULTS: There were 37 females identified in our database who reported any pregnancy or having children. There were 59 pregnancies, 48 (81.3%) of which resulted in live birth. The most common mode of delivery was cesarean delivery. There were five patients with long channel cloaca (>3 cm) and one with cloacal exstrophy that reported 11 total pregnancies, eight of which resulted in live birth. Four cloaca patients in which the native vagina was pulled through were able to conceive spontaneously. Three patients with cloacal anomalies required in vitro fertilization to conceive; one was unsuccessful. No patients who underwent bowel partial vaginal replacement became pregnant. Women with ARM face many unique challenges in assisted reproduction, pregnancy, and delivery owing to their anatomy and associated anomalies. CONCLUSIONS: Women with recto-perineal, recto-vestibular, and cloacas in which the native vagina was pulled through are capable of spontaneous pregnancy. Assisted reproduction, however, may be needed those with more complex anomalies and surgical repairs. LEVEL OF EVIDENCE: IV.

Impact of Pelvic Floor Physical Therapy on Function in Adolescents and Young Adults with Biopsy-Confirmed Endometriosis at a Tertiary Children's Hospital: A Case Series.

STUDY OBJECTIVE: The purpose of this case series is to describe the change in capability to perform self-selected activities in adolescent and young adult patients with chronic pelvic pain and surgically proven endometriosis following pelvic floor physical therapy as part of multidisciplinary treatment. DESIGN: Retrospective case series SETTING: Tertiary care pediatric hospital PARTICIPANTS: Twenty patients with ages ranging from 14 to 22 years and a median age of 16.5 years with biopsy-confirmed endometriosis INTERVENTION: Pelvic floor physical therapy MAIN OUTCOME MEASURE(S): Patient-Specific Functional Scale (PSFS) outcome measure RESULTS: Patients had a clinically significant functional improvement (median score of 6.0 points on the PSFS outcome measure; interquartile range, 3.8-13.5) over the course of care (median number of 12 visits; range 4-48 visits) (P < .001). CONCLUSIONS: Patients with chronic pelvic pain and surgically proven endometriosis experienced significant functional improvement after physical therapy treatment. The results of this case series suggest that physical therapy is a viable additional intervention for adolescents and young adults with chronic pelvic pain and endometriosis and warrants further research.

Vulvar Aphthous Ulcers in an Adolescent After Coronavirus Disease 2019 (COVID-19) Vaccination.

BACKGROUND: Nonsexually acquired genital ulcers have been described among girls who are prepubertal after various viral illnesses due to mucosal inflammation from an immunologic response. Until recently, nonsexually acquired genital ulcers have only been associated with viral infections. CASE: We present a case of an adolescent girl developing nonsexually acquired genital ulcers after both her first and second coronavirus disease 2019 (COVID-19) vaccine doses. Her course followed an expected timeline for severity and resolution of ulcers. CONCLUSIONS: Aphthous ulcers may arise from inflammatory effects of COVID-19 vaccination. Clinical monitoring after COVID-19 vaccination from all formulations should include assessment for nonsexually acquired genital ulcers if vaginal pain is reported.

Interventions to Improve Sexual Health in Women Living with and Surviving Cancer: Review and Recommendations.

Sexual health concerns, both physical and psychological, are common and represent an unmet need among women with and surviving cancer. Sexual challenges and conditions negatively impact body image, satisfaction, relationships, well-being, and quality of life, yet are widely reported to be under-recognized and undertreated. To guide clinical care and future research on sexual function in women with cancer, we performed a scoping review of interventions for sexual health concerns, including sexual function, body image, genitourinary symptoms, and hot flashes. Relevant publications between 2005 and 2020 were identified by searching PubMed with a combination of medical subject headings and keywords. Articles were included if they focused on the aforementioned topics, were primary research publications, and included female cancer survivors. Studies focusing on women receiving hormone therapy for breast cancer were also included. A total of 91 investigations conducted in the US and abroad were reviewed. Most commonly, interventions included a component of psychoeducation, although pharmacologic, exercise, and other approaches have been evaluated. Many studies have focused on survivors of breast or gynecologic cancer, among other sampling and methodological limitations. These limitations underscore the need for more work on this vital survivorship issue. Recommendations for future research in this area are also offered.

Disparities in Female Pediatric, Adolescent and Young Adult Oncofertility: A Needs Assessment.

Advancements in cancer screening and implementation of targeted treatments have significantly improved survival rates to 85% for pediatric and AYA survivors. Greater than 75% of survivors will live to experience the long-term adverse outcomes of cancer therapies, termed late effects (LE), that disrupt quality of life (QoL). Infertility and poor reproductive outcomes are significant disruptors of QoL in survivorship, affecting 12-88% of survivors who receive at-risk therapies. To mitigate risk, fertility preservation (FP) counseling is recommended as standard of care prior to gonadotoxic therapy. However, disparities in FP counseling, implementation of FP interventions, and screening for gynecologic late effects in survivorship persist. Barriers to care include a lack of provider and patient knowledge of the safety and breadth of current FP options, misconceptions about the duration of time required to implement FP therapies, cost, and health care team bias. Developing strategies to address barriers and implement established guidelines are necessary to ensure equity and improve quality of care across populations.

Oncofertility Knowledge and Communication: Comparison Between Medical and Surgical Oncologists and Breast Cancer Patients in Academic Chinese Centers.

Background: As cancer has become a major public health issue in China, fertility preservation remains limited despite the wide application of Assisted Reproductive Technology (ART) throughout the country. Objective: This study aimed to identify gaps in knowledge and communication as well as referrals in the previous year regarding oncofertility among medical and surgical oncologists and breast cancer patients (BCPs) in Chinese academic settings to target areas of needed improvement. Materials and Methods: A WeChat online questionnaire was designed, distributed, and compared between medical and surgical oncology specialists and reproductive age BCPs in academic teaching settings in Shanghai. Results: Sixty-one medical and surgical oncologists and 125 BCPs responded to the survey. 63.3% of oncologists were familiar with the term "oncofertility" compared to 25.6% of BCPs (p < 0.001). Oncologists were more likely to correctly know the costs associated with treatment (59.0 vs. 32.0%, p < 0.001); patient did not have to be married to undergo oncofertility treatment (50.8 vs. 24.8%, p < 0.001). Both oncologists and BCPs were similarly unlikely to know when patients could utilize cryopreserved tissue in the future (37.7 vs. 22.2%, p = 0.056). While oncologists reported they discussed all oncofertility options (41.0%) and offered psychological counseling (98.4%), significantly fewer BCPs reported receiving information on all options and offered counseling (3.2%, p < 0.001 and 85.6%, p < 0.01). Knowledge of oncofertility was the most important predictor for providing and receiving counseling from oncologists [OR = 6.44 (95% CI = 1.59-26.1, p = 0.009] and BCPs (OR = 3.73 95% CI: = 1.36-10.2, p = 0.011). Overall, 57.4% of oncologists referred <10 patients and none referred more than 25 patients in the past year. Conclusion: Data suggests a significant knowledge gap and ineffective communication/comprehension exists between academic Chinese oncologists and BCPs. Continued education and raised awareness are needed to optimize utilization of oncofertility services in China.