Summary

Formulations with no estrogen, like Norethindrone only, or formulations with a higher progestin to estrogen ratio, such as Drospirenone plus Ethinyl Estradiol or Etynodiol Diacetate plus Ethinyl Estradiol, may be more protective for the ACL than formulations with low progestin to estrogen ratios.

Abstract

Introduction

Females are up to eight times more likely to injure their anterior cruciate ligaments (ACLs) than males. While anatomical and biomechanical factors likely contribute to this disparity, hormonal differences have also been found to predispose women to ACL injury. The ACL’s strength is affected by various female hormones such as relaxin and estrogen. Oral contraceptives (OCs) can directly alter these hormone levels, however no study to date has done a comprehensive comparison of differing contraceptive regimens on ACL strength.

Methods

Untreated and pregnant rats were compared to rats treated with one of the five following clinically-used OCs: Norethindrone only, Norethindrone plus Ethinyl Estradiol, Etynodiol Diacetate plus Ethinyl Estradiol, Norgestimate plus Ethinyl Estradiol, and Drospirenone plus Ethinyl Estradiol. Doses were scaled from human doses to account for differences in bioavailabilty and body weight, and OCs were administered daily via oral gavage for four rat estrous cycles (20 days). 42 rats were then sacrificed (6 rats/group), and ACL specimens underwent biomechanical testing and were preloaded to 1N and then preconditioned for 10 cycles at a rate of 0.25mm/s. Strength (MPa) and stiffness (N/mm), and were assessed. ACL strength (MPa) was calculated by normalizing maximum load before failure (N) by ACL cross sectional area (mm2). ACL length before testing (mm), cross sectional area (mm2), and length at maximum load (mm) were also recorded. Readings from the left and right ACLs for each rat were averaged. Data was then analyzed with One-Way ANOVA and post hoc Bonferroni and Holm multiple comparison statistical calculations.

Results

The average strength of ACLs from rats treated with Norethindrone only (42.1 ± 3.5 MPa), Drospirenone plus Ethinyl Estradiol (41.0 ± 4.6 MPa), and Etynodiol Diacetate plus Ethinyl Estradiol (40.8 ± 8.2 MPa) was significantly increased when compared to untreated rats (29.1 ± 4.9 MPa) (p = 0.006, p = 0.015, and p = 0.018 respectively). There was no significant difference with Norethindrone plus Ethinyl Estradiol (38.7 ± 6.7 MPa) and Norgestimate plus Ethinyl Estradiol (34.9 ± 3.6 MPa) OCs. ACL strength directly correlated with each formulation’s ratio of progestin to estrogen potency. The order from strongest to weakest ACLs as well as highest to lowest progesterone to estrogen ratios was Norethindrone only, Drospirenone plus Ethinyl Estradiol, Etynodiol Diacetate plus Ethinyl Estradiol, Norethindrone plus Ethinyl Estradiol, and then Norgestimate plus Ethinyl Estradiol.

Conclusion

Oral contraceptives act to influence ACL strength differently depending on their formulation. Norethindrone only, Drospirenone plus Ethinyl Estradiol, and Etynodiol Diacetate plus Ethinyl Estradiol formulations increased ACL strength when compared to Norethindrone plus Ethinyl Estradiol, Norgestimate plus Ethinyl Estradiol, pregnant, and untreated rat ACLs. Formulations with no estrogen, like Norethindrone only, or formulations with a higher progestin to estrogen ratio, such as Drospirenone plus Ethinyl Estradiol or Etynodiol Diacetate plus Ethinyl Estradiol, may be more protective for the ACL than formulations with low progestin to estrogen ratios, such as Norethindrone plus Ethinyl Estradiol and Norgestimate plus Ethinyl Estradiol.