Hormonal contraceptive use and risk of pancreatic cancer-A cohort study among premenopausal women

The worldwide incidence rate of pancreatic cancer is 10.9 per 100,000 women versus 13.9 per 100,000 men; and pancreatic cancer is relatively rare in young women [ 1 ]. However, the mortality rate of pancreatic cancer is almost identical with its incidence rate [ 2 ], reflecting its high case-fatality rate. Sex-steroid hormone receptors have been detected in both normal and neoplastic human pancreatic tissue [ 3 ]. Estrogen has been found to inhibit the growth of pre-neoplastic pancreatic lesions or transplanted pancreatic carcinoma in rats and progesterone may possess anti-neoplastic properties [ 3 ]. The pancreas is not necessarily considered a target organ of sex steroids, but various clinical and experimental findings demonstrate effects of progesterone on pancreatic endocrine function due to progesterone receptors expressed in islet cells; and reproductive factors possibly play a role in the etiology of pancreatic cancer. [ 4 ][ 5 ]. Today, approximately 140 million women worldwide or 13% of women aged 15–49 years use hormonal contraception.[ 6 ] Thus, determining the relationship between use of hormonal contraception and pancreatic cancer is important given the high prevalence of hormonal contraceptive use and the high case-fatality rate of pancreatic cancer. A majority of previous studies on hormonal contraception and pancreatic cancer have been case-control and cohort studies, and report no association between use of oral contraception and risk of pancreatic cancer. [ 7 – 10 ][ 11 – 13 ][ 14 – 16 ][ 17 ]. However, one prospective cohort study of nearly 120,000 women followed over 14 years found that long-term users of hormonal contraception had a, statistically significant, 72% increased risk of pancreatic cancer compared to never use [ 3 ]. In this study, oral contraception use was self-reported via questionnaires. Moreover, the inclusion of postmenopausal women in the study population could cause bias with regards to the risk of pancreas cancer due to the use of postmenopausal hormone therapy (HT). Some studies suggest that use of HT decreases the risk or has no association to the risk of developing of panceatic cancer.[ 3 , 12 ][ 17 ] Other studies suggest that postmenopausal women alone are at increased risk of pancreatic cancer. [ 11 ] To ensure no bias caused by factors related to the postmenopausal age, we investigated the use of different types of contemporary hormonal contraception and the risk of pancreatic cancer in a large cohort of pre-menopausal women.

From 1995 to 2014 women aged 15–49 years old accumulated 12.9 million person-years of hormonal contraceptive use and 235 pancreatic cancers incidents were recorded. Compared to never users, ever users of any type of hormonal contraception had a relative risk of pancreatic cancer of 0.90 (95% confidence interval (CI) 0.68–1.19) ( Table 1 ). * Adjusted for age, year, education, PCOS, endometriosis, and parity. Current or recent users of any type of hormonal contraception had a relative risk of 1.01 (95% CI 0.72–1.42). No overall association between duration of hormonal contraception use and pancreatic cancer risk was found ( Table 1 ). Neither was long-term use (more than 10 years) of hormonal contraception associated with cancer of the pancreas: relative risk 0.83 (95% CI 0.47–1.50). Compared to never use, former users had a relative risk of 0.80 (95% CI 0.57–1.13), not significantly changing with time since latest use ( Table 1 ). Compared to never users, current or recent use of progestin only contraception showed a relative risk of 1.16 (95% CI 0.79–1.89) and combined oral contraception a relative risk of 0.92 (95% CI 0.62–1.36) ( Table 2 ). The simple and fully adjusted results were almost identical. Additional adjustment for smoking status and body mass index in parous women did not change the estimates. *Adjusted for age, year, education, PCOS, endometriosis, and parity.

In conclusion our study suggests no risk of pancreatic cancer with use of any type of hormonal contraception in premenopausal women. Thus, the risk of pancreatic cancer is not a factor to be considered when assessing the risks and benefits of hormonal contraceptive use.

Since 1960 all citizens in Denmark have had a personal identification number recorded in the Civil Registry that holds records of age, death, and emigration. Data from The Danish Cancer Register (containing histologically verified cancers since 1943) provided information on any malignant disease; the Danish National Patient Register contains clinical diagnoses and surgical codes at discharge from public and private hospitals since 1976, and the National Birth Register information about births since 1973. The National Register of Medicinal Product Statistics contains details of redeemed prescriptions for hormonal contraception and was linked using the personal identification number as the key identifier. Data from the National Register of Medicinal Product Statistics is considered complete from January 1, 1995 and this was consequently the start date of this study. Data was stored and analyzed on servers at Statistics Denmark. The unique personal identification numbers were encrypted ensuring anonymity during the data analyses. All women living in Denmark aged 15–49 years at January 1st, 1995, and those subsequently reaching age 15 years up to December 31st, 2014 were eligible for the study. From the National Register of Medicinal Product Statistics, we obtained information on the date of redeemed prescriptions, the specific Anatomical Therapeutic Chemical code, dose, number of packages, defined daily doses, and route of administration (tablet, patch, IUD, etc.). The use of hormonal contraception was updated daily, with women changing status at time of cessation or switch in type of hormonal contraception used. Gaps between prescriptions of less than 28 days were filled out prospectively.[ 18 ] Hormonal contraceptive use was categorized as current or recent use (cessation within last six months), previous use (cessation more than six months ago) or never use. The levonorgestrel-intrauterine system (IUD) was used for four years, unless pregnancy or another hormonal product was prescribed before the IUD expired. The National Birth Register and Statistics Denmark provided information on potential confounders; parity (0, 1, 2, 3, 4 or >4), age at first birth among parous women (30 years), smoking status among parous women (yes, no, unknown; available since 1991), body mass index among parous women (30, unknown; available since 2004) and completed or ongoing education (elementary school only, high school only, further education but not college/university, college/university education, university education with research qualifications, unknown). The Danish National Patient Register provided information on diagnosis of polycystic ovary syndrome (yes/no) or endometriosis (yes/no). All models were adjusted for these conditions since women with these diseases more often use hormonal contraception. Data was analyzed by Poisson regression using SAS statistical software, version 9.1 (SAS Institute, Inc., Cary, North Carolina) to calculate incidence rate ratios (referred to as relative risk) and 95% confidence intervals. Age was used as a timescale in the Poison regression analyses with 5-year age bands. The study population was followed until a first diagnosis of pancreatic cancer, death, emigration, 50 years of age, or end of follow-up on December 31, 2014, whichever came first. Women were censored permanently at time of cancer diagnosis, infertility treatment, or venous thrombosis. Women were censored temporarily during pregnancy and for six months after delivery. The following time-dependent variables were updated daily: hormonal contraception variables, age, calendar year, parity, age at first birth, and education. The simple adjusted models included hormonal contraception, age, and calendar year. Calendar year was included to account for possible changes in the use of specific types of contraception and in pancreatic cancer incidence during the study period. The fully adjusted models included all the time-dependent and the time-constant variables; polycystic ovary syndrome (ever), and endometriosis (ever). Additional adjustment for body mass index and smoking status and the time of first birth was conducted among parous women with this information. The reference group in each analysis was women who had never used hormonal contraception at a given time during follow-up. Calculated risk ratios will be referred to as relative risks throughout the manuscript, this includes all tables. A search of the PubMed database was performed where relevant articles were identified using the following search terms: “pancreatic cancer”, “pancreatic adenocarcinoma”, “pancreatic neoplasm” combined with “reproductive factors”, “oral contraception”, “exogenous hormone use”. Date of last search was on the 1 st of February 2018. A flow chart further describing the inclusion of studies can be found in the supporting information. ( S1 Fig ). Data was made available through Statistics Denmark and approval obtained from the Danish Data Protection Agency and Health Data Board (previous National Board of Health). According to the Danish Research Ethics Committee Law (§ 8, section 3), ethical approval is not required for register-based studies. Data must be requested from the Danish National eHealth Authority due to legal restrictions on sharing data publicly. Data requests are sent through the application form at: https://sundhedsdatastyrelsen.dk/da/forskerservice/ansog-om-data (the website is in Danish).

(DOCX) Click here for additional data file. Studies assessing the risk of pancreatic cancer in users of hormonal contraception stratified according to study design as case-control studies. (DOCX) Click here for additional data file. Studies assessing the risk of pancreatic cancer in users of hormonal contraception stratified according to study design as cohort studies. (DOCX) Click here for additional data file. Studies assessing the risk of pancreatic cancer in users of hormonal contraception stratified according to meta analyses. (DOCX) Click here for additional data file.