Chapter 1 Introduction

1.1 Background

The decline of the ovarian follicle pool in humans is a natural process. It is associated with reduced fertility in the mid-thirties, irregular menstruation from the mid-forties, and finally, follicle exhaustion and menopause in the early fifties. (Wilkosz et al. 2014) The treatment of cancer can accelerate this process and can cause primary ovarian insufficiency (POI) which is defined as compromised gonadal function before age 40. (Chemaitilly et al. 2017)

It has been shown that female childhood cancer survivors (CCSs) are at a significantly increased risk of developing POI compared to the general population.(Levine et al. 2018; Chemaitilly et al. 2006) While the prevalence of POI in the general population is about 1%, (Torrealday and Pal 2015) it was estimated that 6.3% of female CCSs lose ovarian function within 5 years of cancer diagnosis (one subcategory of POI: acute ovarian failure, AOF) (Levine et al. 2018) and 9.1% will go on experience nonsurgical menopause before age 40 (the other subcategory of POI: nonsurgical premature menopause, NSPM). (Levine et al. 2018)

As female CCSs face a high risk of POI which may cause many distressing chronic conditions such as infertility, osteoporosis, heart disease, and depression (“Primary Ovarian Insufficiency Hormone Health Network” n.d.), the American Society of Clinical Oncology (ASCO) has recommended health care providers inform pediatric patients and their parents or guardians about the risk of developing POI and provide information on fertility preservation (Oktay et al. 2018) such as oocyte and ovarian tissue cryopreservation (Dudzinski 2004). However, discussing fertility preservation with pediatric patients and their families is challenging, especially when the absolute risk of developing POI in the future is unknown. Previous research has identified many cancer treatment-related risk factors of POI (Torrealday and Pal 2015; Chemaitilly et al. 2017; Levine et al. 2018; Clark et al. 2020), but there is a need to build prognostic models for predicting the absolute risk of POI for individual patients.

1.2 Objective

The goal of this study was to estimate the risk of developing POI among female childhood cancer survivors before prespecified ages so that information can be provided for those survivors at high risk who might consider fertility preservation before developing POI.

1.3 Organization

The remainder of the thesis is structured as follows. In Chapter 2, I explore predictors, derived age at event, and conducted the univariate analysis. Chapter 3 addresses the analytical challenges including missing data and censoring. Chapter 4 focuses on model development and evaluation. Finally, the findings, study limitations, and future research directions are presented in Chapter 5.