The Reproductive Window in Young Adult Cancer Survivors

描述（由申请人提供）：不孕不育和卵巢早衰是年轻女性癌症改变生活的后果。然而，年轻成年癌症幸存者（YA幸存者）在癌症治疗后的生殖窗口期尚不清楚。鉴于卵巢癌幸存者的数量不断增加，以及癌症治疗后生育干预措施的出现，明确需要识别和分类癌症后卵巢衰老的模式以及与之相关的临床资料，以协助患者咨询和决策。1000名年龄在18-35岁之间的女性癌症幸存者将在癌症治疗后的不同时间内登记，并随访18个月。首先，该研究将检验抗苗勒管激素（AMH）、促卵泡激素（FSH）和雌二醇（E2）在癌症治疗后的模式在三个广泛的治疗毒性组之间会有所不同的假设。卵巢功能生物标志物水平将从每位参与者的一系列自行收集的干血斑（DBS）样本中进行测量。然后，整个队列的数据将按癌症治疗后的时间建模，并比较轻度、中度和重度治疗毒性组的模式（包括峰值时间、峰值持续时间和卵巢功能下降时间）。目的将证明这些生物标志物可以描述生殖窗口的不同持续时间。其次，在令人兴奋的初步数据的刺激下，该研究将验证这一假设，即这一人群所经历的不成比例的心理困扰与下丘脑对卵巢功能的抑制有关。目的是确定焦虑（由患者报告的症状和唾液皮质醇测量）与黄体生成素（LH）、FSH、E2和AMH之间的关系。下丘脑-垂体-卵巢轴抑制从未在癌症的背景下进行过研究，发现焦虑和卵巢功能之间的关联对未来关于焦虑的干预研究至关重要，以改变生殖健康结果。第三，该研究将生成中度毒性组（包括大多数YA幸存者）卵巢功能窗口的临床风险概况。由于异质性，在该组中没有预测卵巢衰老过程变异性的数据。这一目标将确定在中度毒性组中卵巢功能模式的亚群，其次是与之相关的临床因素。基于PI的K23数据，本提案直接响应NICHD生育能力保存项目的优先事项，开发生物标志物和临床参数，以更好地预测性腺储备，优化和扩大生育能力保存的选择。其意义在于，在癌症背景下估计生殖寿命，以指导患者咨询，个体化风险和保留亲生父母的机会。通过创新地使用社交媒体进行招募、非临床、微创DBS和唾液采集以获取生物样本，该提案克服了研究年轻癌症患者长期存在的关键障碍。1

DESCRIPTION (provided by applicant): Infertility and premature ovarian senescence are life-changing consequences of cancer in young women. Yet, the reproductive window after cancer treatment in young adult cancer survivors (YA survivors) is not known. In light of growing numbers of YA survivors and emergence of promising interventions on fertility after cancer treatment, there is a clear need to identify and categorize patterns of ovarian aging after cancer and the clinical profiles associated with them to assist in patient counseling and decision making. 1000 female YA survivors who are between ages 18-35 will be enrolled at varying durations after cancer treatment and followed for 18 months. First, the study will test the hypothesis that patterns of anti-mullerian hormone (AMH), follicle stimulating hormone (FSH) and estradiol (E2) after cancer treatment will differ among three broad treatment toxicity groups. Ovarian function biomarker levels will be measured from serial self-collected dried blood spot (DBS) samples in each participant. Data from the entire cohort will then be modeled by time after cancer treatment, and patterns (including time to peak, duration at peak and time to decline of ovarian function) will be compared among minimal, moderate and severe treatment toxicity groups. The aim will demonstrate that these biomarkers can depict differential durations of the reproductive window. Second, spurred by exciting preliminary data, the study will test the hypothesis that disproportionate psychological distress experienced by this population is associated with hypothalamic suppression of ovarian function. The aim will determine the association between distress (measured by patient-reported symptoms and salivary cortisol) and luteinizing hormone (LH), FSH, E2 and AMH. Hypothalamic-pituitary-ovarian axis suppression has never been studied in the context of cancer, and discovery of an association between distress and ovarian function would be critical to future intervention studies on distress to modify reproductive health outcomes. Third, the study will generate clinical risk profiles for te window of ovarian function for the moderate toxicity group, which encompasses the majority of YA survivors. Due to heterogeneity, there are no data on predicting variability in the course of ovarian aging within this group. This aim will identify subpopulations in patterns of ovarian function within the moderate toxicity group, followed by the clinical factors that are associated with them. Building on the PI's K23 data, this proposal directly responds to priorities of the NICHD Fertility Preservation Program to develop biomarkers and clinical parameters to better predict gonadal reserve, and optimize and expand options for fertility preservation. The significance lies in estimating the reproductive lifespan in the context of cancer in order to guid patient counseling, individualize risks and preserve opportunities for biologic parenthood. Through innovative use of social media for recruitment and non-clinic- based, minimally invasive DBS and saliva collection for biosample accrual, the proposal overcomes longstanding, critical barriers to studying young adults with cancer. 1