Do Oral Contraceptives Protect Against Anterior Cruciate Ligament Injuries in Female Athletes
Phase: PHASE4
Conditions: Ligament Injury
Sponsor: Cedars-Sinai Medical Center

 
 
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Do Combined Oral Contraceptives Protect Against 
Anterior Cruciate Ligament Injuries in Female Athletes? 
 
April 28, 2025 
 
Natasha Trentacosta MD1, Natasha Schimmoeller MD, MPH, MA2, Melodie Metzger PhD1 
1 Kerlan Jobe Orthopedic Institute  
2 Cedars-Sini Department of Obstetrics and Gynecology 
 
 
 

 
 
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TABLE OF CONTENTS  
 
PROTOCOL SUMMARY ........................................................................................................................ 3 
GENERAL INFORMATION ................................................................................................................... 3 
1.0 BACKGROUND, RATIONALE ....................................................................................................... 4 
2.0 STUDY OBJECTIVES....................................................................................................................... 4 
3.0 STUDY POPULATION ..................................................................................................................... 5 
3.1 Selection of the Study Population ................................................................................................... 5 
3.2 Inclusion Criteria .............................................................................................................................. 5 
3.3 Exclusion Criteria ............................................................................................................................. 5 
3.4 Subject Recruitment ........................................................................................................................ 5 
3.5 Subject Screening and Enrollment ................................................................................................... 5 
4.0 STUDY DESIGN AND METHODS ................................................................................................. 6 
5.0 DATA COLLECTION AND MANAGEMENT ................................................................................ 7 
5.1 Data Procurement ........................................................................................................................... 8 
5.2 Variables Collected .......................................................................................................................... 8 
5.3 Source Documents ........................................................................................................................... 8 
5.4 Data Collection and Storage ............................................................................................................ 8 
5.5 Confidentiality and Security of Data ................................................................................................ 8 
6.0 
DATA AND SAFETY MONITORING ........................................................................................ 8 
6.1 Data and Safety Monitoring Plan ..................................................................................................... 9 
6.2 Quality Control and Quality Assurance............................................................................................ 9 
7.0 STATISTICAL CONSIDERATIONS ............................................................................................... 9 
7.1 Study Outcome Measures ............................................................................................................... 9 
7.1 Sample Size Considerations ........................................................................................................... 10 
8.0 
REFERENCES ............................................................................................................................ 10 
 
 

 
 
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PROTOCOL SUMMARY  
 
Purpose and Knowledge to be 
Gained 
 
• The purpose of this study is to investigate the impact of 
combined oral contraceptive (COC) use on serum relaxin 
levels, ACL laxity, and rate of ligamentous injury among 
collegiate female athletes 
• Previous research suggests COC use may decrease serum 
relaxin levels, which could decrease ACL laxity and 
potentially protect against ACL injury (which is 
disproportionately higher in female athletes vs male 
athletes) 
Research Procedures 
 
• Assessment of baseline contraceptive status and initiation 
of study COC if participant desires 
• Participants will undergo the following assessments at 
baseline and at the four-month time point 
(1) Serum relaxin level 
(2) Knee joint anterior and posterior laxity will be tested 
using a KT-2000 arthrometer (Medmetric Corp, San 
Diego, CA) 
(3) Motion Tracking Analysis 
(4) Reported knee injury during study time period 
Subject Population 
• 150 female collegiate athletes competing in sports 
considered high-risk for ACL tears (basketball, soccer, and 
volleyball)  
• Recruited from surrounding universities (Loyola 
Marymount, Pepperdine) where Cedars-Sinai Kerlan Jobe-
affiliated orthopedic surgeons practice 
• Participants who want to remain on no hormonal 
contraception or want to take study COC  
Duration 
• The study includes 2 in-person visits and one phone 
follow-up.  
• The total study duration is 12 months  
 
GENERAL INFORMATION  
CSMC Co-Investigators  
Natasha Schimmoeller MD, Melodie Metzger PhD 
 
Sponsor/Funder 
Internal Funding 
Collaborating Institutions 
Involved in the Research 
None 
 
 
 

 
 
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1.0 BACKGROUND, RATIONALE  
 
Increased female athletic participation was set forth after the establishment of Title IX.11  With 
this increase in activity came a dramatic rise in ACL injuries, revealing a significant gender 
disparity with women having a 2-to-10 times greater risk of ACL rupture.9  While numerous 
studies have revealed anatomic, neuromuscular and hormonal differences play a role,3, 6, 7 one 
question that has not fully been addressed is the possible protective role of combined oral 
contraceptives (COCs).  
 
Prevalence of COC use among female athletes has been estimated at 40% to 50%, showing a 
significant acceptance of COC use by many female athletes.2, 12  Previous literature suggests that 
fluctuating hormones not only play a role is weakening the structure of the female ACL but also 
increase knee joint laxity, leading to poorer lower extremity biomechanics during sports and 
activities.5, 6 While some risk factors are not modifiable, such as the size of a woman’s ACL or 
femoral notch, the ability to safely alter a female’s hormonal profile to confer a more protective, 
favorable environment may theoretically provide a viable intervention for the female athletic 
community in ACL injury prevention as well as in post-ACL reconstruction rehabilitation. 
 
Thus, advancing our knowledge of the underlying pathophysiological mechanisms of ACL 
injuries will further the development of prevention, rehabilitation and training strategies to 
reduce the risk of sport-related injury, thereby enhancing the beneficial effects of physical 
activity on women's health for all ages. With 4 out of 5 heterosexually active women in the U.S. 
using COC in their lifetime, this research may also contribute to growing evidence of non-
contraceptive benefits of COCs. 
 
2.0 STUDY OBJECTIVES  
 
We plan to investigate the hypothesis that combined oral contraceptives (COCs) reduce serum 
relaxin levels and ligament laxity in collegiate female athletes. Though this study cannot prove 
causality, we will also observe if rate of ligamentous injury in female athletes is reduced among 
women taking COC. Our specific aims are as follows: 
 
Aim 1: To evaluate relaxin levels in female athletes on COC or no hormonal contraceptive 
 
Aim 2: To quantify anterior and coronal plane (varus/valgus) knee laxity between female athletes 
using combined oral contraceptives and those who are not using any hormonal treatment.   
 
Aim 3: To track the rate of ACL and other ligamentous injuries (ruptures / sprains) among 
female athletes and determine if COCs have a protective effect. 
 
 
 
 

 
 
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3.0 STUDY POPULATION  
 
3.1 Selection of the Study Population 
• We aim to recruit a convenience sample of 150 female collegiate athletes competing in 
sports considered high-risk for ACL tears (basketball, soccer, and volleyball)  
• Participants will be from surrounding universities (Loyola Marymount, Pepperdine) 
• These female collegiate athletes will be English-speaking, so there is no need for non-
English speaker consent considerations. If, however, a subject wishes to discuss anything 
in another language, CSMC interpreter services will be requested. 
 
3.2 Inclusion Criteria 
• Female 
• 18 years of age or older 
• Currently playing basketball, soccer, or volleyball at Loyola Marymount or Pepperdine 
• If not currently on COC, regular menstrual cycle occurring every 21-35 days 
 
3.3 Exclusion Criteria  
• Previous ACL injury (Previous ACL injury, on the same knee or the contralateral knee, 
places you at a significantly increased risk of subsequent ACL rupture which would 
provide a confounding effect in our study.  Subsequent treatment of that ACL injury, 
whether with surgery or non-operative management, would also affect subsequent ACL 
injury risk.) 
• Underlying neuromuscular disease 
• For COC use group only: Medical contraindication to COC use 
• History of pregnancy (Excluding previous pregnancies eliminates a potential confounder 
--- women may have lasting changes from carrying a pregnancy in the past.) 
• Desire to conceive in the next year 
 
3.4 Subject Recruitment 
Female athletes will be recruited via two pathways: 
(1) Approached by Dr. Trentacosta, who along with other Cedar Sinai Kerlan-Jobe doctors, 
serve as the team physician for the schools.  
(2) Self-referral via recruitment materials posted in training facility 
 
3.5 Subject Screening and Enrollment 
All female athletes for basketball, soccer and volleyball will be provided an informational flyer 
about our study and be given the opportunity to approach Dr. Trentacosta via in-person meeting, 
telephone or email. Potential subjects who are interested will be consented for the study after 
discussion of the study and continued interest in participation. They will then be asked to 
complete a screening questionnaire evaluating medical, surgical, reproductive, and injury history. 
This screening questionnaire will be returned via email to the study coordinator. 
 
Those meeting above enrollment criteria will continue participation and onboarded for the study 
by the study coordinator.   

 
 
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4.0 STUDY DESIGN AND METHODS 
 
Data will be collected prospectively throughout participant intake and study progression. 
Given the personal nature of women’s contraceptive preferences, we will enroll three categories 
of female athletes: 
(1) Women who are not on hormonal contraception and have no plan to start in the next year 
(2) Women who are not on hormonal contraception and would like to initiate study COC 
(3) Women who are currently on hormonal contraception and would like to switch to study 
COC 
For those participants who would like to start study COC, women will be prescribed a daily oral 
contraceptive containing ethinyl estradiol 20mcg/norethindrone 1mg.  
 
Women will maintain a contraceptive compliance diary via paper or Word document which they 
can submit to us in person or electronically. Orthopedic testing will start during the fourth 
menstrual/COC cycle due to delay in COC effect and theoretical cumulative protective effect of 
COC use. All three groups will undergo below testing to evaluate primary and secondary aims.  
 
Serum Relaxin (Aim 1):  
• Participants will have about 2ccs of blood drawn to measure serum relaxin levels at two 
time points: 
1. Baseline 
2. Fourth month of study participation - menstrual cycle-specific timing: 
▪ Participants not on COC: 
• Luteal phase of their menstrual cycle (Days 14-28) 
• This is when peak relaxin levels are noted to occur 
▪ Participants on COC  
• Pill pack days 14-28 
• Women on COC have suppressed ovulation and thus no true luteal 
phase, but will undergo testing during the same time period 
Joint Laxity (Aim 2):  
• Joint laxity will be tested at two separate time points:  
1. Baseline 
2. Fourth month of study participation – synced with serum collection for relaxin 
level testing.    
• Joint Testing:  
o Each participant’s bilateral knee joint laxity will be tested using a KT-2000 
arthrometer (Medmetric Corp, San Diego, CA) for anterior and posterior laxity.   
o Laxity and biomechanical testing will be done in the athletes’ training room on 
campus. 
o To eliminate inter-rater differences in the laxity measurement, only one examiner 
will conduct all knee laxity measurements.    

 
 
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o With a passive anterior and posterior drawer test at 67N and 87N, an average 
displacement (mm) for three cycles will be determined.    
o A Beighton score will be calculated with goniometer by a one examiner to assess 
generalized hypermobility at each time point. 
 
Motion Tracking Analysis (Aim 2):   
• Participants will be kinematically evaluated using a portable, non-invasive, 3-
dimensional motion capture system (Awinda, Xsens Technologies, The Netherlands).   
• Each athlete will be asked to perform a singled-legged drop while the motion tracking 
system collects and records trunk flexion angle (degrees), hip adduction (degrees), and 
internal/external and coronal plane rotation (both in degrees) of the knee.  
• Data will be collected and averaged over three trials at each of the two time points – 
baseline and 4th month of study participation. 
 
Interval Injury Assessment (Aim 3):   
• Ligamentous injury will be monitored over the entire length of the study, tracking the 
date, location, and mechanism of injury for each event by participant report. Follow-ups 
to ask about any injury will occur weekly at each training room session, or sooner if we 
are contacted by athlete or trainer for a more significant injury that needs to be seen 
urgently in the office by team physician. 
 
Medical History Review: 
• Medical history will be queried for the data points in section 5.2 at the screening visit and 
at Visit #1. 
Schedule of Procedures 
 
 
 
 
All procedures are research related 
Procedures 
Screening 
Visit 
Visit #1 
(4-month visit) 
Phone 
follow-up 
(One year) 
Medical History 
X 
X 
 
Prescribing contraception* 
 
 
 
Blood draw 
(Serum relaxin level) 
X 
X 
 
Joint Laxity Testing 
X 
X 
 
Motion Tracking analysis 
X 
X 
 
Obtain interval medical history 
 
X 
X 
*Only for those who want to be put on study contraception. 
 
 
 
5.0 DATA COLLECTION AND MANAGEMENT 
 

 
 
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5.1 Data Procurement 
• Participant data will be collected by study principal investigator and co-investigators and 
the research coordinator.  
• Participants taking study COC will keep a dairy to indicate daily adherence 
o COC diaries will be reviewed at each visit to assess patterns of day-to-day COC 
use.  
 
5.2 Variables Collected 
The following data points/variables will be collected:  
• ID number 
• Date of birth 
• Medical history 
• Surgical history 
• Menstrual/gynecologic history 
• Medications currently taking 
• Social history 
• Serum relaxin level 
• Laxity measurements: Beighton score and anterior and posterior knee displacement (mm) 
during KT-2000  
• Patterns of day-to-day COC use (i.e., consecutive days of OCP use reported with no more 
than two consecutive days of nonuse) 
• Trunk flexion hip adduction, and internal/external and coronal plane rotation of the knee 
measured during a singled-legged drop using the motion tracking equipment mentioned 
above in section 4.0 (Aim 2).  
 
5.3 Source Documents 
All data for this study will be collected prospectively. Subjects’ EMR or other external sources 
will not be accessed for use in the study.  
 
5.4 Data Collection and Storage  
Study documents will be filled out electronically the day of the visit by the investigator and/or 
coordinator. The documents will be labeled with a unique study ID number rather than any direct 
subject identifier. After signature of the study PI, data will be entered into the secure REDCap 
database by the research coordinator. 
 
5.5 Confidentiality and Security of Data 
Data will be coded; subject identifiers will be removed from the rest of the data and a unique 
study ID number assigned. The list linking identifiers to the study ID number will be kept at 
CSMC and will not be shared externally. This linking list will be kept in case of incidental 
findings. This linking document will be kept on a locked excel sheet that only the PI and research 
coordinator will have access to. 
 
6.0 DATA AND SAFETY MONITORING  
 

 
 
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6.1 Data and Safety Monitoring Plan 
• Only listed study staff will have access to the processed data gathered from the visits.  
• Any analysis of the data will be performed on the de-identified dataset. 
• As above, data from the samples will be kept and stored in the Kerlan Jobe secure 
network only. 
 
6.2 Quality Control and Quality Assurance 
• Dr. Trentacosta will be responsible for the evaluation, analysis, and reporting of the data 
among the co-investigators. 
 
7.0 STATISTICAL CONSIDERATIONS  
 
7.1 Study Outcome Measures 
• Data Analysis: Statistical analysis will be performed using SAS statistical software (SAS 
Institute Inc., Cary, NC, USA) with significance set at p<0.05.  Differences in the two 
timepoints will be evaluated between the two groups. Multiple regression will be used to 
analyze rate of injury as a function of OC use (group), joint laxity, motion analysis, and 
serum relaxion, and additional demographic data. Post-hoc ANOVA, or non-parametric 
alternative, will be used to evaluate continuous variables (joint laxity, motion analysis, 
and serum relaxin levels) between groups. 
• Serum relaxin-2 level will be measured using a Quantikine Human Relaxin-2 
Immunoassay (DRL200). All samples will be run in duplicate and relaxin-2 
concentrations will be calculated from the standard curve. The intra-assay and inter-assay 
coefficients of variation and minimum detection limit will be determined and reported.  
• Joint laxity measurements will be evaluated using the KT-2000 and the Beighton Score.  
The KT-2000 measures anterior and posterior displacement (mm) of the tibia relative to 
the femur when an anterior and posterior load are applied to the tibia. The amount of 
tibial displacement provides information on ACL laxity. The Beighton score is screening 
technique for measuring generalized joint hypermobility.1 It requires the performance of 
5 maneuvers, four passive bilateral and one active unilateral performance: 
1. Passive dorsiflexion and hyperextension of the fifth MCP joint beyond 90°     
2. Passive apposition of the thumb to the flexor aspect of the forearm  
3. Passive hyperextension of the elbow beyond 10°  
4. Passive hyperextension of the knee beyond 10° 
 
5. Active forward flexion of the trunk with the knees fully extended so that the 
palms of the hands rest flat on the floor 
 
The Beighton score is based on a 9-point scale with ≥ 4 considered hypermobile.  
• Continuous measures of trunk flexion hip adduction, and internal/external and coronal 
plane rotation of the knee measured during a singled-legged drop using the motion 
tracking equipment mentioned above in section 4.0 (Aim 2). These outcomes measures 
are all in angles (degrees).  Increased valgus knee motion (in the coronal plane) and 
landing with the femur in adduction and internal rotation has been suggested to 
predispose athletes to injury when landing from a jump.10   
 

 
 
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7.1 Sample Size Considerations 
The primary outcome measure of this study is the rate of ligament injury.  Therefore, our sample 
size requirements were based on this measure.  Previous research indicates female athletes’ risk 
of injury is sport dependent.  In Dragoo et al.’s 2011 analysis, they report a 60% rate of ACL 
injury among basketball players, and a ~30% injury rate among soccer, gymnastics, and lacrosse 
female athletes.4  Whereas field hockey and volleyball had a reported 0% rate of injury.  Thus, 
we believe it is reasonable to estimate that females not taking oral contraceptives will have an 
estimated 30% risk of ligament injury, which we aim to demonstrate a 20% absolute reduction to 
10% risk of injury among females taking OCs.  Assuming equal sizing, based on previous 
studies that demonstrate approximately have of female athletes are on OCs,2 we estimate a total 
sample size of 140 will provide approximately 80% power to detect an ACL Injury rate 
difference of 10% (OC) versus 30% (non-OC). 
 
8.0 REFERENCES 
 
 
1. 
Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis. 
1973;32(5):413-418. 
2. 
Brynhildsen J, Lennartsson H, Klemetz M, Dahlquist P, Hedin B, Hammar M. Oral contraceptive 
use among female elite athletes and age-matched controls and its relation to low back pain. 
Acta Obstet Gynecol Scand. 1997;76(9):873-878. 
3. 
Chandrashekar N, Mansouri H, Slauterbeck J, Hashemi J. Sex-based differences in the tensile 
properties of the human anterior cruciate ligament. J Biomech. 2006;39(16):2943-2950. 
4. 
Dragoo JL, Castillo TN, Braun HJ, Ridley BA, Kennedy AC, Golish SR. Prospective correlation 
between serum relaxin concentration and anterior cruciate ligament tears among elite 
collegiate female athletes. Am J Sports Med. 2011;39(10):2175-2180. 
5. 
Gilmer GG, Roberts MD, Oliver GD. The Relationship between Serum Relaxin Concentrations and 
Knee Valgus. Int J Sports Med. 2020;41(3):182-188. 
6. 
Hansen M, Kjaer M. Sex Hormones and Tendon. Adv Exp Med Biol. 2016;920:139-149. 
7. 
Hashemi J, Chandrashekar N, Mansouri H, Slauterbeck JR, Hardy DM. The human anterior 
cruciate ligament: sex differences in ultrastructure and correlation with biomechanical 
properties. J Orthop Res. 2008;26(7):945-950. 
8. 
Heitz NA, Eisenman PA, Beck CL, Walker JA. Hormonal changes throughout the menstrual cycle 
and increased anterior cruciate ligament laxity in females. J Athl Train. 1999;34(2):144-149. 
9. 
Kiapour AM, Murray MM. Basic science of anterior cruciate ligament injury and repair. Bone 
Joint Res. 2014;3(2):20-31. 
10. 
Lopes TJA, Simic M, Myer GD, Ford KR, Hewett TE, Pappas E. The Effects of Injury Prevention 
Programs on the Biomechanics of Landing Tasks: A Systematic Review With Meta-analysis. Am J 
Sports Med. 2018;46(6):1492-1499. 
11. 
Rights USDoEOoC. Title IX and Sex Discrimination. Available at: 
https://www2.ed.gov/about/offices/list/ocr/docs/tix_dis.html. 
12. 
Torstveit MK, Sundgot-Borgen J. Participation in leanness sports but not training volume is 
associated with menstrual dysfunction: a national survey of 1276 elite athletes and controls. Br J 
Sports Med. 2005;39(3):141-147.