Hormonal fluctuations during the menstrual cycle have been reported to affect athletic performance and injury risk. Altering hormonal levels through contraceptives may impact performance and injury risk in women. The aim of this study is to review the literature on the relationship between hormonal contraceptives (HC), and performance and injury. A literature search resulted in 2267 articles that were screened to 61 articles included in this review. The studies examined showed no consistently significant difference between women athletes taking HC and those who were not in regards to athletic performance and injury risk.HC does not appear to have a significant impact on aerobic performance, anaerobic performance, heat acclimatization or cognition. HC containing antiandrogenic components have been shown to decrease strength gains, but HC not containing antiandrogens do not appear to have this same effect. Similarly, the current literature does not support the use of HC to reduce risk or injury, nor does it seem to increase the risk of injury in the majority of women athletes. One potential subgroup of athletes that may benefit from HC as a prophylactic means of injury prevention are female athletes in the 15-19 year old age group where there is evidence to suggest a protective effect against ACL tear. Overall, hormonal contraceptives do not not appear to have a direct effect on athletic performance or injury prevention in women athletes. Clinicians should not use performance or injury risk as an indication for prescription of hormonal contraception.

Hormonal contraception , Female athletes , Injury , Performance

Porras L, Mangutz NJ, Boyd MO, Newby-Goodman M, Jones JM, et al. (2020) Effects of Hormonal Contraceptives on Non-Bone Related Injury Risk and Athletic Performance in Female Athletes: A Systematic Review of the Literature. Ann Sports Med Res 7(5): 1162.

HC: Hormonal Contraception; OCPs: Oral Contraceptive Pills; OC: Oral Contraception, LARC: Long-acting Reversible Contraception; ACL: Anterior Cruciate Ligament; VO2max: Maximal Oxygen Uptake

Female participation in sport continues to grow, especially at a highly competitive collegiate level. As of 2005, more than 2.9 million girls were participating in high school sports in the United States, equating to a 13% increase from the late 1990s. Meanwhile, collegiate participation had grown by 51% as increased opportunities were provided for these athletes to continue competing after high school [1]. Alongside this trend of increased participation is the ever evolving use of contraception, especially hormonal contraceptives (HC), that may contain derivatives of estrogen and/or progesterone. Statistics provided through the National Survey for Family Growth and the Center for Disease Control and Prevention state that 12.6% of women ages 15-49 used oral contraceptive pills (OCPs), 10.3% used longacting reversible contraception (LARC), and 2.1% used injectable medroxyprogesterone (Depo-Provera). Overall, this age range of women used contraception at a rate of 65% with 25% using a form of HC [2]. Compared to a sample population of elite female athletes, approximately half were using HC [3].

Hormonal fluctuations during the menstrual cycle and athletic performance that have been explored in previous research studies. Several studies report a higher cardiovascular strain during moderate exercise in the mid-luteal phase, when levels progesterone and estrogen are increased [4]. A decrease in time to exhaustion in hot conditions during prolonged exercise has also been shown to occur during the mid-luteal phase, when core temperatures are elevated [5]. Altering hormonal levels in athletes through the use of HC therefore may impact performance in female athletes.

It is also known that female athletes have a higher incidence of certain types of injuries when compared to male athletes [6]. Anterior cruciate ligament (ACL), injuries, for example, are reported as occurring two to nine times more often in female athletes than their male counterparts with teenage female athletes being especially affected [7]. Female soccer players were found to be approximately twice as likely to sustain an ACL injury than their male counterparts [6,7]. There are anatomical and biomechanical differences among the different sexes that contribute to this disparity, but hormonal influence is less well established [8].

Our goal is to review any and all relevant studies completed so that health care providers can have a comprehensive, yet concise reference in providing their patients with evidence based recommendations when counseling women athletes on their options for contraception.

A search was performed for clinically relevant studies examining the relationship between hormonal contraceptives and injury risk and performance in women athletes. PubMed and Cochrane Library databases were searched using the inclusion criteria of “hormonal contraceptives”, “injury”, “performance” and “female athletes”. Exclusion criteria were articles in nonEnglish language, non-hormonal contraception/not distinguished and studies on the effect on bone. Covidence software was used as the primary screening and data extraction tool. After primary screening, two independent reviewers assessed the results and further screened the literature by performing a title and abstract review. After this process was complete, any remaining studies were then further screened by the two independent reviewers by performing full text reviews. Data extraction was summarized in a table outlining a description of the participants, specific exposures, outcomes and key findings of the various studies. Any discrepancies between reviewers regarding decisions on including individual studies were flagged for further review by a third reviewer for final decision. At least two reviewers were required to be in agreement regarding meeting inclusion criteria for a study to move onto the next round of review. Quality assessment of the individual articles was assessed using the Cochrane Risk of Bias Comparison.

2267 articles were selected on initial search and imported into Covidence. 197 duplicate articles were then removed, leaving 2070 articles for initial screening. 1841 studies were deemed to be irrelevant for the scope of this review based on title and abstract screening. This left 229 studies for full text screening of eligibility, of which 110 were excluded on further evaluation. This left 119 studies from the initial pool of 2070 studies from literature search. From there, critical review was performed and which led to a total of 60 articles qualifying for data extraction. Prior to submission for publication, we searched for any recently published and updated articles, leading to 1 additional article being included in final data extraction for a total of 61 articles (Figure 1).

Injury

It is well established that female athletes have a higher incidence of certain types of injuries and different risk factors than their male counterparts [6-8]. Hormonal status has been identified as a potential contributor to this disparity [8]. A total of 29 studies were included in this area of review (Table 1).

Tendons/Ligaments/Joints

Physical changes to tendons and ligaments are observed throughout the female menstrual cycle. Increased levels of the peptide hormone Relaxin-2 were found to correlate to increased ACL laxity. These levels were measured as being highest during the luteal phase of the menstrual cycle in women not taking any form of hormonal contraception. However, when taking HC, these elevated levels were significantly reduced during this time period. These findings seem to propose a potential mechanism in how HC could possibly have a protective role against injuries to the ACL [8].

The relationship between the female sex hormones and connective structures of the MSK system has not been extensively researched. Hansen et al. found that there can be lower rates of tendon collagen synthesis in young HC users. In addition, these users have also been found to have reduced knee joint laxity and a decrease in varying degrees of laxity across the menstrual cycle [9]. It has been found that the high levels of estrogen that occur at the end of the follicular phase and during the ovulatory phase are associated with increased laxity and elevated risk of ACL tear [9]. However, similar structural or mechanical properties with menstrual changes do not appear to affect non-ligamentous connective tissue like the patellar tendon [9]. Additionally, Pokorny et al. reported findings of no significant differences in joint laxity measurements of the knee or the hand between OC users and non-users, although it is notable that their original hypothesis was that OC users would have increased joint laxity compared to the non-users. Additionally, these subjects were tested at one point in time each when determined to be in the non-menstrual phase of their cycle [10].

ACL Injury

Regarding HC and injury risk in female athletes, there has been the most research done surrounding ACL injuries. These injuries have been found to be two to nine times more likely to occur in female athletes than males [6,7]. Additionally, these injuries account for significant time lost from training and competition along with a median total health care utilization cost of $13,403.38 [11].

While not taking a more in depth look into physiologic changes, alteration of other injury risk factors, or temporality, Agel et al. and Liederbach et al., mainly found that there was no difference in rates of ACL injury between OC users and non-users [12,13]. There were some reports of decreased injury rates in these athletes, however, some of this data has not been published for peer review.

ACL laxity and anterior tibial translation are intimately related to ACL injury. Lee et al., and Martineau et al., both 

Figure 1: PRISMA flow chart.

reported a decrease in ACL laxity and a corresponding decrease in anterior tibial translation for HC users [14,15]. Martineau et al. went on to suggest the possibility of using HC as prophylaxis for ACL injury based on their findings. Lee et al., on the other hand, reported an increased risk of injury with this reduction in laxity for HC users, a finding that was unique to their study. It is also important to note that Hicks-Little et al. reported HC users having increased anterior tibial translation from increased ACL laxity, leading to increased risk of injury in this group compared to the non-HC user group [16]. This study, along with an additional publication noted the increased laxity and tibial translation being significantly greater during the follicular +/- ovulatory phase of the cycle compared to the luteal phase [17].

There does appear to be a consensus amongst researchers that risk of ACL tear in the female athlete fluctuates throughout the menstrual cycle, whether on OCPs or not. The time of risk appears to increase and peak as the follicular phase culminates in ovulation, which also happens to correspond with peaking levels of estrogen as mentioned previously, and the time of least risk is during the luteal phase when estrogen levels are at their lowest [16,18-24]. Trojian et al., also made mention of the fact that anterior tibial translation was its greatest during the follicular phase connecting increased ACL laxity, increased translation, peaking levels of estrogen, and the highest risk for ACL tear. Wojtys et al., found that while there was an overall significantly greater than expected occurrence of ACL tears in the ovulatory phase compared to luteal phase for all female athletes, HC use could mitigate this association of the ovulatory phase with increased ACL tear risk [24].

Use of HC may make the time of most risk more predictable

Table 1: Data Extraction Table summarizing the key findings in the individual studies examined

for athletes by regulating the menstrual cycle, giving the athlete the potential to plan training or competition around this if possible [18]. HC use may also affect fluctuations in knee flexion force and knee flexion-extension hysteresis along with ACL elasticity across the cycle, with one study reporting that HC use could diminish or eliminate these fluctuations altogether compared to non-HC users [21]. These findings in addition to other studies regarding HC effects on ligamentous laxity and subsequent degree of anterior tibial translation could support possible protective benefits of HC.

One would then question whether there would be a role of HC prophylaxis for ACL tear. One large case-control study reported that women aged 15-19 years old had the highest incidence of undergoing ACL reconstruction. This group was also less likely to be taking HC compared to the general population [25]. Additionally, when HC users were found to have significantly less anterior tibial translation compared to non-OC users, authors suggested this to be a protective effect justifying prophylactic HC use to mitigate this risk factor [15]. However, these studies suggested an association but was not confirmed. While some studies do support protective benefits of HC use, there is also evidence that shows no significant differences between users and non-users. Lefevre et al., and Ruedl et al., compared both those using and not using HC and found that there were no significant differences in their chances of suffering an ACL tear [22,23]. A recently published study of 165,748 female patients proposed that HC did have a protective effect against ACL tear, specifically in those 15-19 years old as they exhibited a 63% reduction in ACL tear incidence compared to those not using HC. These findings indicate that this younger group of athletes may be subject to different risks and benefits with HC use compared to older cohorts [26].

Overall, the field of research regarding HC and ACL injury in the female athlete is limited. HC may have a limited role in ACL prevention for 15-19 years olds. Additional high powered randomized-controlled studies of rigorous methodology will be required to allow providers to advise patients on these risks. The current body of evidence certainly does not suggest that these athletes are at any more risk of injury while taking HC.

Non-ACL MSK Injury

Although a significant amount of the current primary research into HC and injury risk/incidence in female athletes is focused on ACL injuries, some studies choose to focus on general MSK injuries. This includes traumatic injuries, back pain, ankle sprains, and concussions. In addition, the naturally fluctuating levels of estrogen could change mechanical properties of connective tissue and affect other factors related to injury risk, such as neuromuscular coordination and motor control. For example, one recent RCT by Maged et al. found that HC users had improved aspects of postural balance and stability compared to non-HC users. By stabilizing estrogen levels, it appeared that athletes had improved stability, something the authors suggested could lead to lower rates of injury [27].

Three additional studies by Konin et al., Lloyd et al., and Möller-Nielsen et al., measuring incidence of general MSK injury while taking into account HC status reported findings of lower rates of injury in the HC group compared to the non-HC group [28- 30]. While these studies did have statistically significant findings, it should be noted that they were of a small sample size. Opposing the findings of these studies were those conducted by Agel et al., and Thein-Nissenbaum et al., one regarding injury in general and one on non-contact ACL injury and ankle sprains, found that rates of injury occurrence were not significantly different depending on HC status [12,31].

Two studies from Bryhildsen et al. found that HC status was not associated with either increased prevalence of or severity of low back pain [32,33]. The authors noted a trend of providers recommending these athletes experiencing low back pain to avoid HC, as it was believed to potentially worsen symptoms. These studies did not support this belief.

Female athletes suffer from higher rates of concussions, have worse overall outcomes, and have increased levels of cognitive impairment [34]. Two separate studies by Gallagher et al. and Mihalik et al., though small in size with less than 50 subjects each, found that HC users reported less symptoms overall and had a lesser symptoms severity than their counterparts. It is crucial to note that neither study reported a statistically significant difference in time to return to competition. This could point to improved subjective outcomes and merit further study [35,36].

Chauhan et al., showed a possible increased risk of achilles injury with HC use. Athletes with active and symptomatic Achilles tendinopathy were found to have been more likely to have been using HC [37].

Performance

Previous studies have examined how hormonal fluctuations during the menstrual cycle affect athletic performance with mixed results. The mid-luteal phase of the menstrual cycle in particular seems to have the greatest impact on performance, when levels progesterone and estrogen are increased and core temperature is elevated [44,45]. A total of 32 articles pertaining to HC impact on athletic performance were included in this review.

Aerobic capacity

Maximal oxygen uptake (VO2max), is a widely reported measure of aerobic fitness. VO2 max is the point at which oxygen uptake does not increase (or increases only marginally), when work is increased [46]. Existing studies about HC effect on aerobic capacity have conflicting results, but the overall trend is that there is little to no decrease of VO2max in women athletes taking HC. Several studies found no significant difference in VO2max during exercise testing between women taking HC compared to those who were not taking HC [47-50]. Contrary to these findings, other studies demonstrated a decrease in VO2 max between 2-5.8% during exercise testing [51-53].

In the case that maximal oxygen uptake never occurs, VO2 peak is used to predict VO2max in submaximal exercise models [46]. Studies examining VO2 peak found similar results as VO2 max studies in that there was little to no decrease in VO2 peak between hormonal contraceptive users and nonusers. Of the studies that showed a decrease in VO2 peak, the decrease was modest around 2% even with long term use (>12 months) of HC use [52,52]. Schaumberg et al., found that VO2 peak increased more in HC nonusers after sprint interval training, but HC users had longer sustained increases in VO2,peak at 4 weeks postintervention [55]. It should be noted that different preparations of HC were used with different estrogen and progesterone concentrations in these studies. Furthermore, the sample sizes were small and methods of exercise testing varied widely making the generalization of these results difficult.

Anaerobic capacity

Anaerobic performance is seen in the first seconds to minutes of a high intensity activity [46]. Several studies have examined the effect of hormonal contraceptives on anaerobic capacity of women athletes. There appears to be no net effect on anaerobic capacity between HC users and nonusers at any point during the menstrual cycle [53,56, 57]. Redman et al. examined the effects of triphasic OCPs on anaerobic performance at different points of the menstrual cycle and saw an increased power output in OCP users vs nonusers during the first 10 seconds of rowing during low levels of estradiol and progesterone, which correlated to days 26-28 of the menstrual cycle [58]. There has been no consensus in the literature about hormonal fluctuations during the menstrual cycle for non HC users and the effect on anaerobic performance [58]. One study measured stiffness and foot center of pressure (COP) during hopping in HC users and non-users with the intent of elucidating exogenous estrogen’s effect on the neuromechanics of hopping. Non-HC users saw a 30% higher COP path length at ovulation as well as a 25% increase in COP path velocity. These increases were not seen in HC users suggesting more stability and a correlation to the lower incidence of lower extremity MSK injury seen with HC use [59]. Small sample sizes as well as inconsistency in formulation of HC in that these studies used monophasic and triphasic OCPs. Measurements of anaerobic capacity varied as studies used force-velocity, squat jumps and rowing power to measure anaerobic capacity. Based on the current literature, the net effect of HC on anaerobic performance appears to be negligible.

Strength

The large majority of the literature suggests that hormonal contraceptives have no impact on strength [53, 60-66]. There is a wide array of how strength is measured in these studies including dynamometer measurements of hand grip, quadricep contraction, electromyography, mechanomyography and repetition maximums for different muscles groups. Experience raged from recreational to elite level athletes taking a variety of formulations of HC. Several interesting findings should be noted from studies examining the effect of HC on strength. When caffeine is administered with OCPs, the half life of caffeine is extended, prolonging its effects on the body. Knee flexion power and strength increased during eccentric contractions when caffeine and monophasic oral contraceptives were combined, but had no effect on concentric knee flexion power or strength [67]. Gordon et al., found that, while there was no significant difference in strength, lower extremity torque was more consistent in HC users than non-users postulating that this may be injury protective [63]. In regards to strength, the question of the indirect effect of HC on potentially anabolic hormones has also been examined and largely not found to have a significant impact. High frequency lower extremity strength training program showed no effect of hormonal contraceptives on growth hormone levels, cortisol levels and total body fat mass [68]. According to Bernardes et al., HC users had a small increase in GH release with intermittent exercise, but no effect on performance was seen. The authors postulated that the increase in GH was due to an increase in total estrogens (exogenous and endogenous) [69]. In contrast to these studies, when examining HC that have an antiandrogenic effect, such as formulations with added cyproterone acetate, were shown to minimize strength gains when compared to HC without an anti-androgenic component [48]. Based on the current literature, HC does not appear to have an effect on strength, unless there is an anti-androgenic component of the HC, but this is not a widely available formulation.

Body composition

A review of the literature on hormonal contraception’s effect on body composition lead to conflicting results. A large scale study by Procter-Gray et al. examining 150 distance runners over a 24 month period demonstrated slightly less weight gain, less body fat gain and increase in lean mass in eumenorrheic runners taking HC when compared to those runners who were not taking HC [70]. In contrast to these findings, two smaller scale studies examining the effect of hormonal contraceptives on body composition found no difference between HC users and nonusers. Participants were subjected to strength training, plyometric exercises and high intensity interval training in the form of running and swimming [64,71]. Rickenlund et al., showed that weight gain and increase in fat mass occurred in oligomenorrheic and amenorrheic athletes taking HC, a finding that did not occur in those not taking HC [72]. More studies are needed in his area to elucidate the effect of HC on body composition, particularly the differences between eumenorrheic, oligomenorrheic or amennorheic athletes as the current literature suggests this may have an impact on body composition.

Cognition

It is unclear if estradiol and progesterone fluctuations during the menstrual cycle has an impact on cognitive function based on the results of the current literature. Similarly, there is conflicting data about the effect of hormonal contraceptives on cognitive performance. Baskaran et al. demonstrated that verbal memory and executive function improved in oligo-amenorrheic women athletes who took oral contraceptives over a 6 month period. While this study highlights the effects hormonal contraceptives have on the hormonal state experienced during the female athlete triad, it does not account for eumenorrheic women athletes who are not estrogen deficient [73]. More research is needed in this area to further address the questions of the impact of HC on cognition.

Heat acclimatization

Hormonal fluctuations during the menstrual cycle are known to affect core body temperature, with the core temperature being 0.3-0.5 degrees Fahrenheit higher during the luteal phase compared to the late follicular phase [45]. Studies examining the effect of hormonal contraception on heat acclimation found no difference in between those using HC and those who did not in terms of physiological heat acclimatization [74-78]. Armstrong et al. did show that HC users (combined estrogen-progesterone preparation) had a lower threshold for sweating than injectable contraceptive users and non-HC users, an occurrence that was not seen in elite level cyclists as reported by Lei et al. [75,78]. Another finding came from Minahan et al., that noted the resting core temperature was slightly higher in HC users compared to non-HC users, but that this discrepancy disappeared after 30 minutes of performing exercise in hot ambient temperatures. This study also found that women taking HC had a higher perceived exertion when compared to their non-HC using counterparts [77]. Study sizes ranged from 18 to 36. Different hormonal preparations included oral contraceptives, injectable contraceptives. Participants ranged from inactive to recreational athletes.

Risks

VTE: Increased coagulation is a well known risk associated with HC. This risk is often seen clinically in conjunction with smoking, long periods of immobility, or some other coexisting risk factors [38]. HC use was cited as the most common risk factor for development of VTE in one study, with another stating that these women taking HC were 3-11 times more likely to suffer from DVT compared to those not taking HC [39, 40].

Three of the case studies we reviewed involved athletes taking HC that were found to have inherited thrombophilia-- namely, Factor V Leiden and one case of Factor II Prothrombin. This genetic risk factor was suspected to have been compounded by also taking estrogen-containing HC [39,41,42]. Two of these cases resulted in pulmonary embolism, a diagnosis that carries a significant risk of mortality and morbidity. These athletes not only missed significant time in their training and competition suffered from a life-threatening event that must always be considered in these athletes when presenting with vague respiratory symptoms or non-specific pain [40, 41]. We also found cases reporting on unique presentations of VTE, something that may be more common in this athletic population than the general population. Two cases reviewed reported spontaneous VTE of the subclavian and axillary veins, otherwise known as PagetSchroetter syndrome. This effort thrombosis was the result of high volume repetitive activity in two different softball pitchers. Both were found to have either cervical rib or first rib obstruction, scalene hypertrophy from their significant training load, and HC use. One athlete also had Factor V Leiden mutation present as well [42, 43]. This combination of risk factors should be noted as something to remain aware of when counseling individual patients about possible risks and benefits of HC use. One final case resulted in the diagnosis of left common and external iliac vein compression with associated VTE, a condition known as May-Thurner syndrome, that presented as chronic left hip and groin pain [39]. These cases of venous thromboembolism are an important reminder of the risks of HC and should be considered when deciding whether prescription of HC is indicated.

One of the main goals of the systematic review was to provide the most up-to-date resource possible for providers to counsel their patients, specifically the female athlete population.

In regards to HC effects on injury, the current body of evidence does not support the prophylactic use of HC to reduce risk of injury at this point. It is also important to note that there is not a trend of HC increasing risk of injury in this population, so clinicians should not discourage athletes from taking HC for fear of increasing their risk. While some studies do present evidence demonstrating protective effects of HC, many of these lack the statistical power and quality methodology to support their use in this capacity. Female athletes in the 15-19 year old age group may prove to be an exception for prophylactic protective use against ACL tear, especially if future prospective studies confirm the findings of recently published retrospective data. There does appear to be consensus that ligamentous laxity fluctuates throughout the menstrual cycle. Given the overall body of evidence, there appears to be potential for more research to further characterize this relationship between HC and injury incidence.

There does not appear to be a direct relationship, negatively or positively, with HC use an athletic performance in women athletes. Some literature exists demonstrating a modest decrease in aerobic capacity, but other studies demonstrate no difference between HC users and non users. Similarly, HC does not appear to have a significant impact on anaerobic performance, heat acclimatization or cognition. HC containing antiandrogenic components have been shown to decrease strength gains, but HC not containing antiandrogens do not appear to affect strength.

Overall, we found that there is a lack of well controlled, high powered studies in this field. By nature, studies pertaining to HC are difficult to design. The ability to conduct double-blinded RCT is difficult due the fact that many athletes are using HC primarily for its contraceptive purposes. It would present an ethical dilemma if potential subjects were receiving a placebo in place of HC. A large portion of these articles are retrospective and observational as well. This relies heavily on recall by subjects when it comes to questionnaires completed as a part of a study, introducing the potential for recall bias.

Regarding injury, HC does not appear to offer definitive protective benefit. Some evidence does exist to suggest a potential protective effect, but this must be considered in the context of several other studies finding no significant difference between HC users and non-users. Much of the current research is focused on ACL injuries, where there appears to be a clear connection between varying risk of injury depending on menstrual cycle phase. This peak risk tends to exist in the follicular and ovulatory phase, corresponding to the point of maximal estrogen levels. These levels are known to be stabilized by HC, and this supports the need for further exploration in this area to provide a robust amount of support if clinicians were to consider HC use for injury prevention. Being a higher risk population, 15-19 year olds may be considered for prophylactic protective use with careful assessment of their unique risk and expected benefit profile, but universal prophylactic use amongst all ages cannot be recommended at this time.

In terms of athletic performance, HC appears to have little to no effect on athletic performance in the areas of aerobic capacity, anaerobic capacity, strength, body composition, cognition and heat acclimatization. Some studies indicate a small decrease in VO2max and VO2peak. HC formulations that do not have an anti- androgenic component do not appear to impact strength. For these reasons, it is our recommendation that clinicians should use this information to educate patients to make an informed decision about what is best for their unique situation and desire for contraception.

We would like to acknowledge contributions made by Sarah Wright, Clinical Librarian and GME Specialist at the University of North Carolina. There were no other forms of support from pharmaceutical or industry sources, as well as no no sources of funding received for the completion of this work. The authors have no conflicts of interest to note or industry relationships to disclose.

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