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The Menstrual Cycle May Affect
Anterior Knee Laxity and the Rate of
Anterior Cruciate Ligament Rupture
A Systematic Review and Meta-Analysis
Jeremy S. Somerson, MD*
Ian J. Isby, BS*
Mia S. Hagen, MD
Downloaded from http://journals.lww.com/jbjsreviews by BhDMf5ePHKbH4TTImqenVFDg6RAyiLhS7c0bNvcLrAdyOh9ICeapzpXx/INFoz1pDG3tFA25eN0= on 12/08/2019
Christopher Y. Kweon, MD
Albert O. Gee, MD
Investigation performed at the
Department of Orthopaedics and
Sports Medicine, University of
Washington, Seattle, Washington
COPYRIGHT © 2019 BY THE
JOURNAL OF BONE AND JOINT
SURGERY, INCORPORATED
JBJS REVIEWS 2019;7(9):e2 · http://dx.doi.org/10.2106/JBJS.RVW.18.00198
Abstract
Background: Women have a higher risk of anterior cruciate ligament (ACL)
tears than men, the causes of which are multifactorial. The menstrual cycle
and its hormonal effect on the knee may contribute to knee laxity and ACL
injury. This work reviewed published studies examining the effects of the
phases of the menstrual cycle on anterior knee laxity and the rate of ACL tears.
Methods: A systematic review with meta-analysis and meta-regression was
performed. Studies with data comparing the menstrual cycle phase with
ACL injury or anterior knee laxity were included for analysis. Data with regard
to patient demographic characteristics, anterior knee laxity, ACL injury, and
menstrual cycle phases were extracted from the included studies.
Results: In this study, 1,308 search results yielded 396 articles for review, of
which 28 met inclusion criteria. Nineteen studies of knee laxity with 573
combined subjects demonstrated a mean increase in laxity (and standard
deviation) of 0.40 6 0.29 mm in the ovulatory phase compared with the
follicular phase and a mean increase in laxity of 0.21 6 0.21 mm in the luteal
phase compared with the follicular phase. Nine studies examining ACL tears
with 2,519 combined subjects demonstrated a decreased relative risk (RR) of
an ACL tear in the luteal phase compared with the follicular and ovulatory
phases combined (RR, 0.72 [95% confidence interval, 0.56 to 0.89]). There
were no differences in ACL tear risk between any of the other phases.
Conclusions: An increased risk of an ACL tear does not appear to be
associated with periods of increased laxity in this meta-analysis. Although
this suggests that hormonal effects on an ACL tear may not be directly
related to increases in knee laxity, the methodologic heterogeneity
between published studies limits the conclusions that can be drawn and
warrants further investigation.
Level of Evidence: Prognostic Level III. See Instructions for Authors for a
complete description of levels of evidence.
I
n 1972, Title IX of the Education pate in sports. The years since have seen a
Amendments was passed into law in dramatic increase in sports participation by
the United States, creating equal women1. Epidemiologic data have shown
opportunity for women to partici- a 2 to 4 times increased risk of anterior
*Jeremy S. Somerson, MD, and Ian J. Isby, BS, contributed equally to this work.
Disclosure: There was no source of external funding for this study. On the Disclosure of Potential
Conflicts of Interest forms, which are provided with the online version of the article, one or more of the
authors checked “yes” to indicate that the author had a relevant financial relationship in the
biomedical arena outside the submitted work (http://links.lww.com/JBJSREV/A504).
1
 | Me n s t r u a l Cy c l e Ma y Af f e c t An t e r i o r Kn e e L a x i t y a n d t h e R a t e o f An t e r i o r Cr u c i a t e L i g a m e n t Ru p t u r e
cruciate ligament (ACL) tears in women
than in men2-5. Considering the effects
of an ACL tear on the quality of life,
financial cost of care, and long-term
sequelae, it is important to identify
causes for disparity in tear risk between
sexes. Understanding the associations
between the menstrual cycle and injury
risk is of interest both to the individual
athlete and to researchers studying the
relative importance of ACL risk factors.
Women may experience acute
increases in anterior knee laxity during
their menstrual cycle, which may lead to
an ACL injury6-10. Estrogen, progester-
one, and relaxin are believed to play a
role in laxity and injury rates throughout
the menstrual cycle. Evidence of recep-
tors for these hormones on ACL tissue
indicates that they may alter biochemi-
cal, neuromuscular, and biomechanical
characteristics of the knee and ACL11-19.
Two prior systematic reviews had
been published at the time that this
review was initiated. In 2006, Zazulak
et al.20 analyzed 9 studies and concluded
that the menstrual cycle may have an
effect on the anterior-posterior laxity of
the knee. Since then, 11 new investiga-
2 SEPTEMBER 2019
tions have been published1,7,21-29. In
2007, Hewett et al.30 concluded that the
6 studies that they reviewed showed an
increase in tear risk in the preovulatory
half of the menstrual cycle. A subsequent
systematic review and meta-analysis by
Herzberg et al.31 was published in 2017.
The authors were unable to perform a
meta-analysis on the incidence of ACL
injury and the menstrual cycle, as only 5
studies were included. Four additional
studies relating to the incidence of ACL
injury and the menstrual cycle32-35 were
included in this review, allowing for
meta-analysis. Other, smaller system-
atic reviews by Belanger et al.36 and
Balachandar et al.37 were also published
prior to this review, although these
reviews included fewer publications
than the present work.
The goal of this study was to syn-
thesize all available literature on ante-
rior knee laxity and ACL tear rates
throughout the menstrual cycle, given
the increase in available data since the
prior reviews. Through a systematic
review and meta-analysis, we hypothe-
sized that there would be phases of the
menstrual cycle associated with greater
anterior knee translation, with a subse-
quently increased ACL tear risk.
Materials and Methods
Search Strategy
A systematic review using the Preferred
Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guide-
lines identified all literature that inves-
tigated an association between the
menstrual cycle and ACL injury and/or
anterior knee laxity in women. The full
search strategy is described in the
Appendix. Bibliographies of collected
studies were searched for any relevant
research. The systematic review, data
extraction, and risk-of-bias assessment
were performed by the coprimary author
in consultation with the senior authors.
The initial search returned 1,308
results (Fig. 1). Abstracts, unpublished
literature, and duplicates were excluded,
yielding 396 papers for review. Study
selection for inclusion in the systematic
review was first determined by title or
abstract and then by full-paper review.
Studies comparing the menstrual cycle
phase with ACL injury or anterior knee
laxity were included. Exclusion criteria
Fig. 1
Literature search results.
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Fig. 2
Illustration of the phases of the menstrual
cycle.

included use of oral or hormonal con-
traceptives, irregular menses, and prior
ACL injury or contralateral ACL injury.
There were no non-English articles that
met inclusion criteria. In total, 28 arti-
cles were selected for meta-analysis, with
9 examining ACL tears and 19 examin-
ing anterior knee laxity.
Data Preparation
Data were collected from female subjects
with normal menstrual cycles, as defined
by individual studies. The stages of the
menstrual cycle were defined as the fol-
licular phase (days 1 to 9), the ovulatory
phase (days 10 to 14), and the luteal
phase (days 15 to 28) (Fig. 2). These
cutoffs were chosen to allow for the

TABLE I Patient Characteristics for Each Laxity Study*

Laxity Study Study Level of
Study Subjects Population Age† (yr) Period Method Method Quality Design Country Evidence

Belanger39 18 Athlete 20 (NA) Other methods KT2000 Poor Cohort United States II
(2004)
Beynnon2 17 NA 22 (17 to 29) Hormones KT1000 Fair Cohort United States II
(2005)
Carcia62 (2004) 20 Non-athlete 21 (18 to 26) Menstrual event KT2000 Poor Cohort United States II
Deie57 (2002) 158 NA 22 (21 to 23) Hormones KT2000 Fair Cohort Japan II
Eiling21 (2007) 11 Athlete 16 (NA) Hormones KT2000 Fair Cohort Germany II
Heitz40 (1999) 7 Athlete 27 (21 to 32) Hormones KT2000 Fair Cohort United States II
Hertel22 (2006) 14 Athlete 19 (NA) Hormones KT1000 Fair Cohort United States II
Hicks-Little23 28 Athlete NA (18 to 23) Other methods KT1000 Fair Cohort United States II
(2007)
Hoffman1 28 Non-athlete 22 (NA) Hormones KT2000 Fair Cohort United States II
(2008)
Karageanes58 26 Athlete 16 (14 to 18) Other methods KT2000 Fair Cohort United States II
(2000)
Khowailed24 14 Non-athlete 26 (NA) Hormones KT2000 Fair Cohort United States II
(2015)
Lee25 (2013) 10 Non-athlete 25 (18 to 30) Hormones KT2000 Fair Cohort United States II
Park7 (2009) 26 Athlete 23 (NA) Hormones KT2000 Fair Cohort Canada II
Pollard26 12 Athlete 25 (NA) Hormones KT1000 Fair Cohort United States II
(2006)
Romani59 20 Athlete 26 (NA) Menstrual event KT2000 Fair Cohort United States II
(2003)
Shultz60 (2005) 22 Non-athlete 23 (19.6 to 30.5) Hormones KT2000 Fair Cohort United States II
Shultz27 (2010) 66 Non-athlete 22 (NA) Menstrual event KT2000 Fair Cohort United States II
Shultz10 (2011) 64 Athlete NA (18 to 30) Menstrual event KT2000 Fair Cohort United States II
Van Lunen61 12 Athlete 24 (NA) Menstrual event KT2000 Fair Cohort United States II
(2003)

*NA 5 not available. †The values are given as the mean, with the range in parentheses.

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TABLE II Methods for Determining Laxity and Phase for Each ACL Tear Study*
No. of
ACL Case Year Phase Study Level of
Study Tears Range Population Age† (yr) Method Quality Study Design Country Evidence

Adachi45 18 2006 to 2006 Athlete 16 (11 to 18) Other Poor Case series Japan IV
(2008) methods
Agel32 (2006) 8 2000 to 2002 Athlete NA Menstrual Poor Cohort United II
event States
Arendt38 58 1996 to 1999 Athlete NA Other Poor Retrospective United III
(2002) methods cohort States
Beynnon42 46 2000 to 2004 Non-athlete 36 (15 to 53) Hormones Fair Case-control United III
(2006) States
Myklebust33 9 1993 to 1996 Athlete 22 (NA) Other Poor Cohort Norway II
(1998) methods
Ruedl43 61 2006 to 2008 Non-athlete 39 (14 to 53) Other Poor Case-control Austria III
(2009) methods
Slauterbeck34 37 NA Athlete NA Hormones Poor Retrospective United III
(2002) cohort States
Wojtys35 28 NA Athlete 23 (NA) Other Poor Case series United IV
(1998) methods States
Wojtys46 51 NA Athlete 28 (15 to 46) Hormones Poor Case series United IV
(2002) States

*NA 5 not available. †The values are given as the mean, with the range in parentheses.

standardization and comparison of
study results and were consistent with
prior research and reviews on the
topic1,2,7,20,32-34,38-40.
Included studies were examined
for outcomes of anterior knee laxity and
ACL injury rate presented by the men-
strual cycle phase. Study year, sample
size, patient characteristics (age, athlete),
and methods for determining laxity and
phase were recorded for each eligible
study (Tables I and II). ACL laxity was
measured using KT1000 or KT2000
arthrometers (Medmetric)41. The
means and standard errors of laxity by
phase were recorded for each eligible
study. When the standard error was
unavailable, either the standard devia-
tion (SD) or the width of the 95%
confidence interval (WCI) was recorded
and was used to calculate the standard
error (SE) as SE 5 SD/√N for the
standard deviation and SE 5 WCI/(2 3
1.96) for the width of the confidence
interval. In some articles, multiple
means and standard error laxity values
were presented for each phase (e.g.,
measurements on multiple days, with
different forces, or on different knees);
these were averaged to yield a single
mean and standard error for each study
and phase. Data used for laxity analysis
are available in the Appendix.
The ACL injury rate was defined as
the ACL tear rate. Various methods were
utilized by studies to determine an ACL
tear, including magnetic resonance
imaging, physician or athletic trainer
examination, the National Collegiate
Athletic Association database, referral to
a health-care facility for ACL recon-
struction, and unspecified methods.
The number of subjects with an ACL
tear categorized by menstrual phase was
recorded. Two studies did not separate
ACL tears between the follicular and
ovulatory phases and presented only the
total number of ACL tears for the 2
phases combined42,43.
Studies established the phase of the
menstrual cycle by various methods,
which we classified as hormones, a
menstrual event, or other methods. The
hormones group included studies that
used serum, urine, or saliva measure-
ment of menstrual hormones to deter-
mine the phase of the cycle. Estradiol
and progesterone were most frequently
measured, with some studies including
luteal hormone and follicle-stimulating
hormone. The menstrual event group
used the onset of menses or ovulation
kits, with or without adjunct calendar
calculation, to determine phase. The
other methods group was represented by
studies that used questionnaires, patient
recall, a menstrual calendar, basal body
temperature with a calendar, or an
unspecified calculation.
Data Analysis and Statistical Methods
The analysis included 2 distinct groups
of outcomes: anterior knee laxity and
ACL tear rate. For each laxity study, we
presented the mean and the standard
error of the laxity by menstrual phase.
Laxity was defined in millimeters of
anterior translation using an arthrome-
ter. For each ACL tear study, we pre-
sented the number and percentage of
ACL tears by phase.
The differences in mean laxity
between each pair of phases (ovulatory
minus follicular, luteal minus follicular,
and luteal minus ovulatory) were used as
the effect size for the meta-analysis of
laxity. The standard errors of the differ-
ences were approximated by √(SE12 1
SE22), where SE1 and SE2 were standard
errors of the means in the 2 compared

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phases. This standard error value was a
conservative choice, as we speculated
that the laxities in the 2 phases were
positively correlated; thus, we would
expect the actual standard error of the
difference of the means to be smaller.
The numbers of ACL tears were
compared in 4 groups: (1) the ovulatory
phase compared with the follicular
phase, (2) the luteal phase compared
with the follicular phase, (3) the luteal
phase compared with the ovulatory
phase, and (4) the luteal phase compared
with the combined ovulatory and fol-
licular phases. For each of these pairs, the
first phase was the outcome phase, and
the second phase was the reference
phase. The effect size for each of the 4
phase comparisons in the ACL tear risk
was the proportion (p) of ACL tears in
the outcome phase among tears in the
outcome and reference phases com-
bined. The effect size was analyzed on
the logit scale (log[p/(1 2 p)]). The
variance of logit(p) was calculated by
standard methods implemented by the
function escalc of the R package meta-
for44. The statistical methods for effect
size calculation and meta-analysis are
described in detail in the Appendix.
Results
Anterior Knee Laxity
Nineteen studies were included in the
laxity analysis. There were a combined
573 subjects, with a range of 7 to 158

TABLE III Mean Laxity by Phase for Each Laxity Study

Follicular Ovulatory Luteal

No. of No. of No. of No. of Standard

Study Subjects Measurements Laxity* Measurements Laxity* Measurements Laxity* Error Source

Belanger39 18 1 4.60 6 0.31 1 4.80 6 0.31 1 4.70 6 0.31 Confidence

(2004) interval
Beynnon2 17 2 8.85 6 0.62 1 8.90 6 0.63 2 8.60 6 0.46 Standard
(2005) deviation
Carcia62 20 2 5.55 6 0.32 2 5.60 6 0.36 2 5.62 6 0.32 Standard
(2004) deviation
Deie57 (2002) 16 2 5.55 6 0.23 2 6.05 6 0.20 2 6.05 6 0.23 Standard
deviation
Eiling21 (2007) 11 2 4.50 6 0.44 1 5.10 6 0.27 1 4.60 6 0.27 Standard
deviation
Heitz40 (1999) 7 1 5.60 6 0.51 1 6.40 6 0.62 1 7.00 6 0.63 Standard
deviation
Hertel22 14 1 4.51 6 0.45 1 4.70 6 0.40 1 4.17 6 0.43 Standard
(2006) deviation
Hicks-Little23 28 1 5.11 6 0.38 1 5.76 6 0.32 1 5.63 6 0.46 Standard
(2007) deviation
Hoffman1 28 4 5.33 6 0.39 3 5.36 6 0.40 8 5.53 6 0.38 Standard
(2008) deviation
Karageanes58 26 2 4.75 6 0.26 2 4.84 6 0.33 2 4.86 6 0.26 Standard
(2000) error
Khowailed24 12 1 4.18 6 0.08 1 5.75 6 0.14 — — Standard
(2015) error
Lee25 (2013) 10 3 5.30 6 0.47 1 5.90 6 0.54 3 5.43 6 0.48 Standard
deviation
Park7 (2009) 26 1 4.78 6 0.33 1 5.20 6 0.33 1 4.62 6 0.30 Standard
deviation
Pollard26 12 1 4.20 6 0.23 1 4.20 6 0.23 1 4.20 6 0.23 Standard
(2006) deviation
Romani59 20 1 5.80 6 0.36 1 5.70 6 0.40 1 6.10 6 0.38 Standard
(2003) deviation
Shultz60 22 15 3.77 6 0.33 15 3.95 6 0.33 30 4.12 6 0.32 Standard
(2005) deviation
Shultz27 66 6 6.63 6 0.27 — — 8 6.67 6 0.28 Standard
(2010) deviation
Shultz10 64 1 6.70 6 0.24 — — 1 7.40 6 0.26 Standard
(2011) deviation
Van Lunen61 12 1 6.02 6 0.36 1 6.36 6 0.36 1 6.10 6 0.39 Standard
(2003) error

*The values are given as the mean and the standard error, in millimeters.

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subjects per study. Eleven of the 19
studies involved athletes, 6 involved
non-athletes, and 2 did not specify ath-
letic status. All but 2 studies showed the
mean age of their subjects, and 9 studies
showed their age ranges. To measure
anterior knee laxity, 15 studies used the
KT2000 arthrometer and 4 studies used
the KT1000 arthrometer.
The mean laxity by phase for each
study is shown in Table III. When ana-
lyzing these results with meta-analysis
(Fig. 3), the largest mean effect size was
found in the difference between the
ovulatory phase and the follicular phase.
Anterior knee laxity was greater in the
ovulatory phase compared with the fol-
licular phase by a mean difference (and
standard deviation) of 0.40 6 0.29 mm
(95% confidence interval [CI], 0.11 to
0.69 mm) per study, a significant dif-
ference (p 5 0.007). In their study,
Khowailed et al.24 had noticeably larger
mean laxity differences between the
ovulatory phase and the follicular phase,
as well as much smaller standard devia-
tions compared with other investigations;
thus, this study was considered an outlier.
Investigating its possible effects on the
data further, 2 sensitivity analyses (1 with
the assumption that the data published in
the Khowailed study were standard errors
rather than standard deviations and
1 with the Khowailed study excluded
from the meta-analysis) confirmed the
difference between ovulatory and follic-
ular phases, although the estimated effect
was smaller (mean and standard error,
0.25 6 0.11 mm; p 5 0.03) when the
Khowailed study was excluded.
A second finding was that the mean
anterior knee laxity in the luteal phase was
0.21 6 0.21 mm (95% CI, 0.00 to
0.42 mm) greater than in the follicular
phase (p 5 0.049). The difference
between laxity means (and standard
errors) in the luteal and ovulatory phases
was small (20.09 6 0.11 mm) and not
significant (p 5 0.4). Except for the
Khowailed study, the effects in the meta-
analyses were relatively homogenous across
the analyzed studies (I2 5 0% for the luteal
minus follicular meta-analysis, 0% for the
luteal minus ovulatory meta-analysis, and
0% for the 2 sensitivity analyses carried out
for the ovulatory minus follicular meta-
analysis, but 51% when including the
Khowailed study without standard errors
in the ovulatory minus follicular meta-
analysis). Tests for publication bias were

Fig. 3
Meta-analysis of the mean laxity by phase for each study. RE 5 random effects, O 5 ovulatory, F 5 follicular, and L 5 luteal.

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TABLE IV ACL Tears by Phase for Each ACL Tear Study*

Phases†
Study Total No. of Tears Follicular Ovulatory Follicular and Ovulatory Luteal

Adachi45 (2008) 18 2 (11%) 13 (72%) 15 (83%) 3 (17%)

Agel32 (2006) 8 4 (50%) 1 (12%) 5 (62%) 3 (38%)
Arendt38 (2002) 58 25 (43%) 12 (21%) 37 (64%) 21 (36%)
Beynnon42 (2006) 46 NA NA 34 (74%) 12 (26%)
Myklebust33 (1998) 9 2 (22%) 1 (11%) 3 (33%) 6 (67%)
43
Ruedl (2009) 61 NA NA 35 (57%) 26 (43%)
Slauterbeck34 (2002) 37 25 (68%) 1 (3%) 26 (70%) 11 (30%)
Wojtys35 (1998) 28 4 (14%) 8 (29%) 12 (43%) 16 (57%)
Wojtys46 (2002) 51 13 (25%) 24 (47%) 37 (73%) 14 (27%)

*NA 5 not available. †The values are given as the number of tears, with the row percentage in parentheses.

not significant, except for the ovulatory Meta-regressions of the above- nificant association, except that studies
minus follicular analysis, which was driven described effect sizes using patient and published later were associated with a
by the Khowailed study. method characteristics showed no sig- larger ovulatory-follicular differential

Fig. 4
Meta-analysis of the combined numbers and percentages ofACL tears by phase for each study. RE 5 random effects, O 5 ovulatory, F 5 follicular, and L5 luteal.

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(0.82-mm increase for a 10-year increase
in publication year; p 5 0.002). How-
ever, this association disappeared when
the Khowailed24 study was excluded or
its standard deviations were converted to
standard errors (see Appendix for meta-
regression results).
ACL Tear
Nine studies were included in the ACL
tear analysis32-35,38,42,43,45,46 (Table II).
The studies involved a combined 2,519
subjects, with a range of 18 to 2,026
subjects per study. A total of 316 ACL
tears were recorded across the 9 studies,
with a range of 8 to 61 tears per study.
Seven of the 9 studies involved an ath-
letic population. Of the 9 studies, 6
showed the mean age, and 4 showed the
age range of subjects. Three studies were
classified in the hormones group, 1 study
was classified in the menstrual event
group, and 5 studies were classified in
the other methods group. Data were
collected from 1993 to 2008, with 3 of
the 9 studies not specifying the date of
data collection.
The numbers and percentages of
ACL tears by phase for each study are
shown in Table IV. When combining
results in the meta-analyses (Fig. 4), the
largest mean effect was found for the
comparison of the luteal phase and
the combined follicular and ovulatory
phases. A mean 36% (95% CI, 28% to
45%) of ACL tears per study were in the
luteal phase, which is 14% less than
would be expected if there were no dif-
ference in the risks between the 2 phases
(and accounting for the duration of the 2
phases). Thus, patients in the luteal
phase have 0.72 times the risk of an ACL
tear compared with patients in the fol-
licular and ovulatory phases (relative risk
[RR], 0.72 [95% CI, 0.56 to 0.89]; p 5
0.002). The effects were heterogeneous
across all studies (I2 5 50% and tau 5
0.4 for the meta-analysis comparing the
luteal phase with the follicular and
ovulatory phases, 84% for the meta-
analysis comparing the ovulatory phase
with the follicular phase, 60% for the
meta-analysis comparing the luteal
phase with the follicular phase, and 70%
8 SEPTEMBER 2019
for the meta-analysis comparing the
luteal phase with the ovulatory phase).
Tests for publication bias were not
significant.
Meta-regressions of the above-
described effect sizes using patient and
method characteristics showed no sig-
nificant association, except that studies
with other methods of phase detection
were significantly associated with a
larger portion of ACL tears during the
luteal phase compared with studies with
the hormones method (odds ratio [OR],
1.90 [95% CI, 1.16 to 3.11]; p 5 0.01).
All meta-regression results are available
in the Appendix.
Discussion
The associations of the menstrual cycle
with ACL laxity and ACL injury remain
controversial. A better understanding
of risk factors for injury is of interest
for athletes, clinicians, and researchers.
These results indicate that anterior knee
translation is lowest during the follicular
phase of the menstrual cycle (days 1 to 9)
compared with the ovulatory phase
(days 10 to 14) or the luteal phase (days
15 to 28). After a meta-analysis of the
included studies, anterior knee transla-
tion was 0.40 mm greater in the ovula-
tory phase compared with the follicular
phase, and it was 0.21 mm greater in the
luteal phase compared with the follicular
phase. The difference between the ovu-
latory and follicular phases was still sig-
nificant even when eliminating the
outlier study (Khowailed et al.24). With
regard to the ACL tear rate, the lowest
risk of tear was in the luteal phase
compared with the combined follicular
and ovulatory phases (RR, 0.72). The
follicular and ovulatory phases were
combined for this portion of the anal-
ysis as they represent the preovulatory
half of the menstrual cycle (days 1
through 14 of 28) during which an
injury event might occur. The overall
quality of evidence based on the
GRADE (Grading of Recommenda-
tions Assessment, Development and
Evaluation) working group was very
low47, indicating that additional higher-
quality studies are needed.
These findings on anterior knee
translation are similar to the prior review
published in 2006 by Zazulak et al.20.
They determined anterior knee transla-
tion to be lowest in the follicular phase
and greatest in the ovulatory phase. A
review by Herzberg et al.31, published
in 2017, after the conclusion of this
investigation, identified 13 studies on
ACL laxity and the menstrual cycle and
performed a meta-analysis on 6 of those
studies. They found that ACL laxity was
greater in the ovulatory phase compared
with the follicular phase, but did not
detect a difference between the other
phases. In this current study, a similar
result demonstrated that the mean laxity
difference between the follicular and
ovulatory phases was greater than the
mean laxity difference between the fol-
licular and luteal phases. However, a
significant difference between the ovu-
latory and luteal phases was not found.
Comparing analysis methods, Herzberg
et al.31 assumed a 0.5 correlation
between pairs of measurements in dif-
ferent phases, whereas this current
analysis was more conservative and
assumed no correlation between mea-
surements in different phases. This re-
sulted in larger within-study standard
deviation values; thus, this analysis was
less likely to reject a conclusion of no
difference between phases. This analysis
was able to identify and include more
studies and data than Herzberg et al.31,
and was performed with and without the
outlier results from the study by Kho-
wailed et al.24. Additionally, this study
included meta-regression analyses that
attributed the between-study heteroge-
neity to specific differences.
Our findings of an increased risk of
an ACL tear in the preovulatory phase is
in agreement with a prior review pub-
lished in 2007 by Hewett et al.30. A
review of 5 articles on ACL tears during
the menstrual cycle by Herzberg et al.31
suggested that ACL tear risk was lowest
in the luteal phase; however, they were
unable to perform a meta-analysis on
data from the literature. Our meta-
analysis of the 9 included studies
provides quantitative evidence to
· VOLUME 7, ISSUE 9 · e2
 Me n s t r u a l Cy c l e May Af f ec t An t e r i o r Kn e e L a x i t y a n d t h e R a t e o f An t e r i o r Cr u c i a t e L i g am en t Ru p t u r e
substantiate the findings of both Herz-
berg et al.31 and Hewett et al.30. It is
important to note that the significant
finding of a lower risk of ACL tears in the
luteal phase is small (RR, 0.72 [95% CI,
0.56 to 0.89]; p 5 0.002) and may not
translate to a meaningful clinical differ-
ence. Additionally, no difference in the
ACL injury risk was present between any
of the other phases (Fig. 4).
Anterior knee laxity has been
proposed as a risk factor for ACL
injury3,4,48-50, with increased laxity
placing participants in landing and
movement motions that are associated
with an increased risk of a noncontact
ACL tear6-8,10,17,29,51-54. Based on the
anterior knee translation data, the risk of
an ACL tear should therefore be lowest
in the follicular phase of the menstrual
cycle. However, this contradicts our
findings on the ACL tear rate, in which
there was predominantly nonsignificant
variation between phases, apart from a
significantly lower risk in the luteal
phase. It was originally hypothesized
that if laxity increased the risk for an
ACL tear, the risk of tear should cor-
relate with times of increased laxity.
The results of these meta-analyses did
not demonstrate a correlation between
the 2 variables. This may suggest that
the effect that hormones have on ACL
tear rates is via a mechanism other than
increasing laxity. Knee laxity is higher
during the ovulatory phase, which
includes the surge in estradiol, a hor-
mone that has been shown to decrease
fibroblast proliferation and collagen
synthesis55. During the luteal phase,
progesterone starts to rise and its level is
higher than the estradiol level. Proges-
terone has been shown to increase
fibroblast proliferation and collagen
synthesis, which can explain the
decrease in laxity during this phase and a
potential protective effect against an
ACL tear56. During the follicular phase,
serum estradiol and progesterone levels
are at their lowest. However, the estra-
diol level stays higher than the proges-
terone level, which may explain the
presence of ACL injuries during this
phase.
SEPTEMBER 2019 · VOLUME 7, ISSUE 9 · e2
We chose to categorize the method
of phase classification into 3 broad
groups: hormones, a menstrual event,
and other methods. Based on metho-
dology and prior evidence, the hor-
mones studies seemed to have the
greatest likelihood of accurately identi-
fying the menstrual phase, and the other
methods studies (employing tactics such
as patient recall) may be less accurate in
identifying the subject’s phase. In our
analysis of the effect of study character-
istics, the studies classified as using other
methods to determine the subject’s
phase had a significantly increased risk
(OR, 1.90 [95% CI, 1.16 to 3.11]; p 5
0.01) of an ACL tear during the luteal
phase compared with the hormones
group of studies. This result is under-
standable when the data for the per-
centage of tears taking place in the luteal
phase were compared among the 3
groups. The 3 studies in the hormones
group were within 10% of each other,
whereas the other methods group had
a range from ,20% to .60% of tears
occurring in the luteal phase (see
Appendix).
This review and meta-analysis had
several limitations. The inherent varia-
bility in the menstrual cycle made it
difficult to standardize and study. We
did not investigate other factors, such as
body mass index, that could influence
hormone levels. Many of the studies
have methodologies that have different
accuracy in classifying the subject’s
phase and varying levels of study quality.
There was no uniform definition of an
ACL tear. Additionally, despite best
efforts to group these studies by meth-
odology for comparison, the methodo-
logical differences inherently create bias
in the investigation. Several of the
studies utilized athlete subjects, with
results that may not be generalizable to
the broader female population. Finally,
although this review utilized PRISMA
guidelines for performing this system-
atic review and meta-analyses, it is pos-
sible that studies were missed if they
were unpublished, were not available
online, or were not discovered in the
reviewed journals.
|
In conclusion, this study found that
anterior knee translation is greater in the
ovulatory or luteal phases of the menstrual
cycle. This may be explained by the
increase in knee laxity observed with higher
levels of estrogen in the ovulatory phase.
However, the risk of ACL rupture was
greatest in the preovulatory phase, when
relatively lower levels of progesterone are
present. The overall effect of cyclical vari-
ation on rates of ACL injury is small. Fur-
ther research efforts should be focused on
assessing for a possible time-delay effect of
hormones along with other factors that
may have a greater effect on ACL injury
differences between men and women, such
as neuromuscular activation patterns, knee
kinematics, or other anatomical differences
that are possibly modifiable to decrease the
rate of ACL tears in women.
Appendix
Supporting material provided by the
authors is posted with the online version of
this article as a data supplement at jbjs.org
(http://links.lww.com/JBJSREV/A505).
Jeremy S. Somerson, MD1,
Ian J. Isby, BS2,
Mia S. Hagen, MD2,
Christopher Y. Kweon, MD2,
Albert O. Gee, MD2
1Department of Orthopaedic Surgery and
Rehabilitation, University of Texas
Medical Branch, Galveston, Texas
2Department of Orthopaedics and Sports
Medicine, University of Washington,
Seattle, Washington
E-mail address for J.S. Somerson:
jeremysomerson@gmail.com
ORCID iD for J.S. Somerson:
0000-0001-7272-5922
ORCID iD for I.J. Isby:
0000-0002-1081-6092
ORCID iD for M.S. Hagen:
0000-0002-8297-2991
ORCID iD for C.Y. Kweon:
0000-0001-6864-4599
ORCID iD for A.O. Gee:
0000-0001-9422-204X
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11