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

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.

Premature ovarian insufficiency is the onset of premature menopause in individuals less than 40-years-old.

Previous research has shown that there is a higher risk of premature ovarian insufficiency in adolescent and young adult cancer survivors, due to the toxicity of cancer treatments on reproductive organs.

Prior research was limited in its applicability by having small sample sizes, only including childhood cancer, excluding young adults, and studying fewer types of cancer.

This study was conducted using a large population-based approach, on all females aged 15–39 years old with cancer in Ontario, Canada from 1995 to 2015.

We found that there was nearly a 2.5 times greater risk of premature ovarian insufficiency in cancer survivors compared patients without cancer.

Compared to patients without cancer, this risk was highest for survivors of leukemia (14 times higher risk), followed by breast cancer (4 times higher risk), lymphomas (2–4 times higher risk), and thyroid cancer (1.2 times higher risk).

There is no increased risk in melanoma survivors.

The risk was higher in individuals diagnosed with cancer at a later age (30–39 years), with a risk 3 times higher than the population without cancer, while a younger age of diagnosis (15–29 years) carries a risk only 1.75 times higher than the population without cancer.

These results should help improve healthcare provider and patient understanding of the risk of premature ovarian insuficiency in young cancer survivors, and guide counseling at the time of cancer diagnosis and during survivorship on future reproductive function.