Premature ovarian insufficiency in female adolescent and young adult survivors of non-gynecological cancers: a population-based cohort study

Abstract

Background The risk of premature ovarian insufficiency (POI) is increased in adolescent and young adult (AYA) cancer survivors, with the prevalence depending on cancer diagnosis, treatment, and patient factors. Prior studies are limited by sample size and type of cancer included. The objective of this study was to assess the risk of POI in female AYA survivors of non-gynecologic cancers, using a population-based approach. Methods This population-based retrospective cohort study comprises 21,666 females, 15–39 years old, diagnosed with a single non-gynecologic cancer in Ontario, Canada from 1995 to 2015. Through health administrative data linkage, participants were followed until their 40th birthday, December 31, 2018, bilateral oophorectomy, loss of health insurance eligibility or death. Each cancer survivor was matched to 5 females who were not diagnosed with cancer (unexposed, n = 108,330). Women with bilateral oophorectomy or a prior menopause diagnosis were excluded. POI was identified through use of the ICD-9 code for menopause (ICD9-627). Modified Poisson regression models were used to calculate the adjusted relative risk (aRR) of POI for AYA cancer survivors compared to unexposed individuals, adjusted for income, parity, age, and immigration status. Results The occurrence of POI was higher in survivors of AYA cancer versus unexposed patients (5.4% vs. 2.2%). Survivors of AYA cancer had an increased risk of POI relative to unexposed patients (aRR 2.49; 95% CI 2.32–2.67). Risk varied by type of cancer: breast (4.32; 3.84–4.86), non-Hodgkin’s lymphoma (3.77; 2.88–4.94), Hodgkin’s lymphoma (2.37; 1.91–2.96), leukemia (14.64; 10.50–20.42), thyroid (1.26; 1.09–1.46) and melanoma (1.04; 0.82–1.32). Risk varied by age at time of cancer diagnosis, with a higher risk among females diagnosed at age 30–39 years (3.07; 2.80–3.35) than aged 15–29 years (1.75; 1.55–1.98). Conclusions AYA survivors of non-gynecologic cancers are at an increased risk of POI, particularly survivors of lymphomas, leukemia, breast, and thyroid cancer. The risk of POI is increased for those diagnosed with cancer at an older age. These results should inform reproductive counseling of female AYAs diagnosed with cancer.

Previous cancers in women diagnosed with premature ovarian insufficiency: A nationwide population‐based case–control study

“…To our knowledge, no previous population‐based study has investigated the prevalence of previous cancer in women with POI. However, studies investigating the prevalence of POI in female cancer survivors in specific cancer types exist, and they have reported highly variable figures 20,21,27,28 …”

“…The cumulative risk for a Finnish woman to receive a breast cancer diagnosis until the age of 40 years in 1953–2017 was 0.32%, 17 and our results do not significantly differ from these results at 0.2% of breast cancer cases within POI patients and 0.1% within controls. In a population‐based study by Flatt et al., the adjusted relative risk of POI after breast cancer was 4.32 (95% CI 3.84 to 4.86) in adolescent and young adult women when the diagnosis of POI was based on the ICD‐9 code for menopause before the age of 40 27 . In ovarian cancer patients, especially in those with high‐grade serous epithelial tumors, estrogen is contraindicated in clinical practice.…”

“…However, studies investigating the prevalence of POI in female cancer survivors in specific cancer types exist, and they have reported highly variable figures. 20,21,27,28 Our study has some limitations. Details on cancer treatments are not available in the registers used.…”

Fertility Preservation in Adolescents and Young Adults With Cancer: A Case-Based Review

“…Hence, all women with previous exposure to such agents should be evaluated for infertility, regardless of cumulative dose and possibly even before identifying difficulty with conception, because of chemotherapy potentially resulting in diminished ovarian reserve. [57][58][59][60] If diminished ovarian reserve is identified, oocyte retrieval should be considered, particularly if the patient is not yet ready to contemplate a pregnancy. Education of cancer survivors regarding the concept of premature ovarian failure and a fertility window is essential, particularly as AYA cancer survivors often move away from their primary treatment site and may need to advocate for themselves as they find new health care providers who may not be as familiar with late effects of cancer therapy.…”

Fertility preservation before and after cancer treatment in children, adolescents, and young adults

“…For females, cancer treatments can differentially impact fertility through accelerated ovarian aging of the finite oocyte pool, 13,14 impaired uterine function, 15 disruption of the hypothalamic–pituitary–ovarian axis, 16 and/or cardiopulmonary morbidity 17 (Figure 1). Overall, female childhood cancer survivors childhood and AYA cancer survivors are less likely to have a live birth (hazard ratio [HR] childhood cancer , 0.82 [95% confidence interval (CI), 0.76–0.89]; standardized birth ratio AYA cancer , 0.5 [95% CI, 0.49–0.62]) 18,19 and more likely to have infertility (relative risk [RR] childhood cancer , 1.5 [95% CI, 1.2–1.8]; RR AYA cancer , 1.3 [95% CI, 1.2–1.4]) 20–22 and primary ovarian insufficiency (POI) (RR childhood cancer , 13.2 [95% CI, 3.26–53.5]; RR AYA cancer , 2.5 [95% CI, 2.3–2.7]) 23–26 compared to females without cancer.…”