The Effects of Hormonal Contraceptives on Incidence of ACL Injury Within Menstrual Cycle Phases

Anterior Cruciate Ligament Rupture Clinical Trial

Official title:

The Effects of Hormonal Contraceptives on Incidence of ACL Injury Within Menstrual Cycle Phases

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04986267
• Other study ID #: Buckley_2021
• Status: Completed
• Start date: May 31, 2021
• Est. completion date: May 31, 2024

Study information

• Verified date: June 2024
• Source: University of South Australia
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The aim of this study is to investigate how hormonal contraceptives affect ACL rupture incidence within menstrual cycle phases. It is thought hormones such as estrogen and progesterone (which fluctuate throughout the normal menstrual cycle) play a role in the laxity of ligaments within the body. It is hypothesised that around the time of ovulation the ACL undergoes increased laxity, leaving it more likely to be injured. This study will look at the phase of the menstrual cycle in which the ACL injuries occur and whether there are differences due to the use and type of hormonal contraception participants may be using (such as Combined oral contraceptive, Mirena, Implanon), which can modify the levels of circulating estrogen and progesterone.

This study involves participants completing an anonymous electronic survey after presenting to a sports or orthopaedic clinic with an ACL rupture. The survey collects information about participant's current ACL injury and any previous knee injuries; typical menstrual cycle patterns and the use of hormonal contraception; and history of sports participation. Responses will be analysed to look for similarities and differences in ACL injury occurrence by menstrual cycle phase and hormonal contraceptive use.

The study hypotheses are:

1. Hormonal contraceptives that are known to reduce ovulatory rises in estrogen will have the most consistent pattern of ACL rupture incidence across all phases of the menstrual cycle.

2. There will be a mitigated risk of ACL rupture in the preovulatory phase of the menstrual cycle, relative to the other phases, in women using hormonal contraception compared to those not using hormonal contraception

3. There will be a higher proportion of ACL ruptures during the preovulatory phase of the menstrual cycle in non-hormonal contraceptive users.

Description:

Anterior Cruciate ligament (ACL) rupture has been observed at higher rates in females than males during sporting competition, particularly during the preovulatory phase of the menstrual cycle. During the menstrual cycle, estrogen secretion varies from 10 to 100 fold throughout the cycle. A possible explanation for the ACL injuries being observed in the preovulatory phase, is that increases in estrogen levels increases the laxity of the ACL, predisposing it to risk of rupture. Studies investigating knee joint laxity, concluded that increased joint laxity was associated with an increased risk of ACL injury. In addition, measurement of knee laxity found no changes in laxity over time in males, but greater anterior displacement of the knee during the preovulatory phase of the menstrual cycle compared with the ovulatory and postovulatory phases in women.

Use of hormonal contraception typically maintains estradiol levels at ~25 pg/ml and decreases the ovulatory rise in estrogen. A study of the use of hormonal contraceptive in alpine skiers with ACL rupture reported that 74% of women were in the preovulatory phase (vs 26% in the postovulatory), experienced an ACL rupture. However, in women with ACL rupture in the preovulatory phase, 72.5% of the women were not using a hormonal contraceptive. A recent systematic review suggested an association between hormonal fluctuations and ACL injury and that hormonal contraceptives offer 20% reduction in risk of injury. Multiple modalities of hormonal and contraceptive control are available to females within Australia, but the efficacy of different hormonal contraceptives for reducing the risk of ACL rupture is unknown.

This study aims to investigate: 1) whether there are differences in risk of an ACL rupture incidence within menstrual cycle phases in females using different types of hormonal contraception. 2) whether there are differences in the pattern of ACL rupture incidence within menstrual cycle phases in females using vs not using hormonal contraception. 3) whether ACL rupture incidence in female athletes not using hormonal contraceptives are more prevalent during the pre-ovulatory phase of the menstrual cycle.

The study will use a cross-sectional design, with data being collected in women presenting at sports medicine or orthopaedic clinics with ACL rupture. On presentation at the clinic with ACL rupture, the study will be introduced to patients by a clinician and they will be shown a recruitment flyer that includes a QR code. On scanning the QR code patients will be taken to a RedCap survey website that they can enter an email in to receive, via automated reply email, a Participant Information Sheet and link to an anonymous study survey. The survey will take approximately 7 minutes to complete and asks questions about how the participants ACL injury occurred, any previous knee injuries, their menstrual cycle phase that the injury occurred in, their usual menstrual cycle characteristics, their use of hormonal contraceptives and the main sport they play.

Injury data will be analyzed according to menstrual cycle phase to confirm whether the preovulatory phase presents higher risk of ACL rupture than the ovulatory/postovulatory phase. Data will be stratified by hormonal contraception use and type to evaluate whether the injury occurrence pattern within the menstrual cycle differs by hormonal contraceptive use, such that the anticipated higher incidence in the preovulatory phase is mitigated with hormonal contraceptive use (and type).

The study hypotheses are:

1. Hormonal contraceptives that are known to reduce ovulatory rises in estrogen will have the most consistent pattern of ACL rupture incidence across all phases of the menstrual cycle.

2. There will be a mitigated risk of ACL rupture in the preovulatory phase of the menstrual cycle, relative to the other phases, in women using hormonal contraception compared to those not using hormonal contraception

3. There will be a higher proportion of ACL ruptures during the preovulatory phase of the menstrual cycle in non-hormonal contraceptive users.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: May 31, 2024
• Est. primary completion date: May 31, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Presenting to a sports or orthopaedic clinic with an acute ACL rupture of their knee that occurred within the last 3 months

Related Conditions & MeSH terms

• Anterior Cruciate Ligament Injuries
• Anterior Cruciate Ligament Rupture
• Rupture

Intervention

Other:
• ACL Rupture
Female, aged 18-40 years of age with an acute ACL rupture of the knee that occurred within the last 3 months, who presented to a sports or orthopaedic clinic

Locations

Country	Name	City	State
Australia	UniSA Allied Health and Human Performance	Adelaide	South Australia

Sponsors (1)

Lead Sponsor	Collaborator
University of South Australia

Country where clinical trial is conducted

Australia, 

References & Publications (10)

Beynnon BD, Shultz SJ. Anatomic alignment, menstrual cycle phase, and the risk of anterior cruciate ligament injury. J Athl Train. 2008 Sep-Oct;43(5):541-2. doi: 10.4085/1062-6050-43.5.541. No abstract available. — View Citation

Chidi-Ogbolu N, Baar K. Effect of Estrogen on Musculoskeletal Performance and Injury Risk. Front Physiol. 2019 Jan 15;9:1834. doi: 10.3389/fphys.2018.01834. eCollection 2018. — View Citation

Deie M, Sakamaki Y, Sumen Y, Urabe Y, Ikuta Y. Anterior knee laxity in young women varies with their menstrual cycle. Int Orthop. 2002;26(3):154-6. doi: 10.1007/s00264-001-0326-0. Epub 2002 Apr 5. — View Citation

Fox A, Bonacci J, Hoffmann S, Nimphius S, Saunders N. Anterior cruciate ligament injuries in Australian football: should women and girls be playing? You're asking the wrong question. BMJ Open Sport Exerc Med. 2020 Apr 9;6(1):e000778. doi: 10.1136/bmjsem-2020-000778. eCollection 2020. — View Citation

Herzberg SD, Motu'apuaka ML, Lambert W, Fu R, Brady J, Guise JM. The Effect of Menstrual Cycle and Contraceptives on ACL Injuries and Laxity: A Systematic Review and Meta-analysis. Orthop J Sports Med. 2017 Jul 21;5(7):2325967117718781. doi: 10.1177/2325967117718781. eCollection 2017 Jul. — View Citation

Mishell DR Jr, Thorneycroft IH, Nakamura RM, Nagata Y, Stone SC. Serum estradiol in women ingesting combination oral contraceptive steroids. Am J Obstet Gynecol. 1972 Dec 1;114(7):923-8. doi: 10.1016/0002-9378(72)90098-1. — View Citation

Myer GD, Ford KR, Paterno MV, Nick TG, Hewett TE. The effects of generalized joint laxity on risk of anterior cruciate ligament injury in young female athletes. Am J Sports Med. 2008 Jun;36(6):1073-80. doi: 10.1177/0363546507313572. Epub 2008 Mar 7. — View Citation

Ramesh R, Von Arx O, Azzopardi T, Schranz PJ. The risk of anterior cruciate ligament rupture with generalised joint laxity. J Bone Joint Surg Br. 2005 Jun;87(6):800-3. doi: 10.1302/0301-620X.87B6.15833. — View Citation

Renstrom P, Ljungqvist A, Arendt E, Beynnon B, Fukubayashi T, Garrett W, Georgoulis T, Hewett TE, Johnson R, Krosshaug T, Mandelbaum B, Micheli L, Myklebust G, Roos E, Roos H, Schamasch P, Shultz S, Werner S, Wojtys E, Engebretsen L. Non-contact ACL injuries in female athletes: an International Olympic Committee current concepts statement. Br J Sports Med. 2008 Jun;42(6):394-412. doi: 10.1136/bjsm.2008.048934. — View Citation

Wojtys EM, Huston LJ, Boynton MD, Spindler KP, Lindenfeld TN. The effect of the menstrual cycle on anterior cruciate ligament injuries in women as determined by hormone levels. Am J Sports Med. 2002 Mar-Apr;30(2):182-8. doi: 10.1177/03635465020300020601. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	ACL Injury Menstrual Cycle Phase, sensitivity analysis (Contact vs Non-Contact)	Examine robustness considering contact vs non contact injuries.	Baseline
Other	ACL Injury Menstrual Cycle Phase, sensitivity analysis (Previous knee injury)	Examine robustness considering previous serious knee injury (yes vs. no)	Baseline
Other	ACL Injury Menstrual Cycle Phase, sensitivity analysis (playing history/level)	Examine robustness considering player competition level	Baseline
Other	ACL Injury Menstrual Cycle Phase, sensitivity analysis (menstrual cycle status)	Examine robustness considering menstrual cycle status	Baseline
Other	ACL Injury Menstrual Cycle Phase, sensitivity analysis (menstrual cycle recall confidence)	Examine robustness considering menstrual cycle recall confidence	Baseline
Other	ACL Injury Menstrual Cycle Phase, sensitivity analysis (age)	Examine robustness considering age	Baseline
Other	ACL Injury Menstrual Cycle Phase, sensitivity analysis (BMI)	Examine robustness considering body mass index	Baseline
Primary	ACL Injury Menstrual Cycle Phase by Hormonal Contraceptive Type	In which phase of the menstrual cycle did the ACL injury occur, by hormonal contraceptive type (including non-use reference)	Baseline
Secondary	ACL Injury Menstrual Cycle Phase by Hormonal Contraceptive Use	In which phase of the menstrual cycle did the ACL injury occur, by hormonal contraceptive use vs. non-use	Baseline
Secondary	ACL Injury Menstrual Cycle Phase Overall	In which phase of the menstrual cycle did the ACL injury occur (pooled group)	Baseline