Oral contraceptives cause evolutionarily novel increases in hormone exposure: A risk factor for breast cancer

Abstract

Background and objectives: In the evolutionary past, women spent most of their reproductive lives either pregnant or in lactational amenorrhea, and rarely menstruated. The current pattern of frequent menses, and the associated increase in endogenous hormonal exposure, has been implicated in the current breast cancer epidemic. It is not known, however, whether oral contraceptives further increase, or actually decrease, hormonal exposure over one menstrual cycle. Here, we examined variation in hormonal exposure across seven oral contraceptive (OC) formulations, and produced the first quantitative comparison of exogenous versus endogenous hormone exposure. Methodology: Data from 12 studies of serum estradiol (E2) and progesterone (P4) were aggregated to create a composite graph of endogenous hormone levels over one menstrual cycle in European or American women (age 19-40 years). Pharmacokinetic package insert data, also from Western women, were used to calculate exposures for hormones in seven different OC formulations. Endogenous and exogenous hormone levels were compared after adjusting for the relative binding affinity (RBA) of progestin to the progesterone receptor and ethinyl estradiol (EE) to the estrogen receptor. Results: After adjusting for RBA, median ethinyl estradiol exposure across 28 days in the OCs was 11.4 nmol/l, similar to median E2 exposure. One formulation, however, was 40% higher in ethinyl estradiol exposure relative to median endogenous estradiol. Median exposure from progestins in OCs (1496 nmol/l) was 4-fold higher than the median endogenous exposure from P4 (364 nmol/l). Exposure from OC progestins ranged from one sixtieth to 8-fold median endogenous P4 over 28 days. Conclusions and implications: Given that breast cancer risk increases with hormonal exposure, our finding that four widely prescribed formulations more than quadruple progestin exposure relative to endogenous progesterone exposure is cause for concern. As not all formulations produce the same exposures, these findings are pertinent to contraceptive choice. We also identify critical gaps in the provision of relevant data on pharmacokinetics and carcinogenicity by drug manufacturers.

Keywords: breast cancer; estrogen; oral contraceptives; progesterone.

Figures

Figure 1.

(A) Daily endogenous estradiol exposure observed over 28 days in nmol/l based on data from 12 studies of women in the US and Europe (N = 181 women and 302 ovulatory cycles). Solid line and circles are the mean endogenous estradiol exposure with 95% confidence intervals. Dashed line is median exposure. (B) Daily endogenous progesterone exposure observed over 28 days in nmol/l based on data from 12 studies. Solid line and circles are the mean endogenous progesterone exposure with 95% confidence intervals. Dashed line is median exposure

Figure 2.

Daily 17-β-estradiol exposure in non OC-users compared to daily ethinyl estradiol exposure, observed over 28 days measured in nmol/l. Open circles are endogenous E2 daily exposure, solid circles are unstandardized exogenous EE daily exposure and solid squares are exogenous EE exposure standardized by the RBA of EE to the estrogen receptor, which is 190. EE exposure is reported for each of seven OC formulations detailed in Table 1

Figure 3.

Daily progesterone exposure in non OC-users compared to daily progestin exposure, observed over 28 days, measured in nmol/l. Open circles are endogenous P4 daily exposure, solid circles are unstandardized exogenous progestin daily exposure and solid squares are exogenous progestin exposure standardized by the RBA of each progestin to the progesterone receptor, which varies for each progestin (Table 2). Progestin exposure is reported for each of seven OC formulations detailed in Table 1. There are five types of progestins: levonorgestrel (LNG), norethindrone (NE), desogestrel (DES), norgestimate (NGM) and drospirenone (DRSP)

Figure 4.

(A) Over a 28-day cycle, total mean ± SD in nmol/l of endogenous 17-β-estradiol exposure in non-OC-users compared to total exogenous EE exposure from women taking each each of seven OC formulations detailed in Table 1. Open bars are unstandardized EE exposure, and solid bars are EE exposure standardized by the RBA of EE to the estrogen receptor. (B) Over a 28-day cycle, total mean ± SD in nmol/l of endogenous progesterone exposure in non-OC-users compared to exogenous progestin exposure in women taking each OC (A-G). Open bars are unstandardized progestin exposure, and solid bars are progestin exposure standardized by RBA of each progestin to the progesterone receptor (Table 2)