Given the sex differences in musculoskeletal injury risk and the growing number of active young women, the role of estrogen in
musculoskeletal function in men and women is a rapidly increasing area of research.
This article will highlight important developments, controversies, and unknowns in the relationship between estrogen and musculoskeletal function.
It will focus on the direct and indirect effects of estrogen on musculoskeletal function, as well as how these changes affect performance, adaptation, and injury risk in an active population. Let's get started.
Beyond its role as a sex hormone, estrogen has crucial functions in the development, maturation, and aging of bone, muscle, and connective tissues.
In young women, estrogen is produced from cholesterol in a series of reactions within the ovaries. The final reaction in the process is the conversion of testosterone to estradiol by the enzyme aromatase. In men and postmenopausal women, this reaction commonly occurs in adipose tissue which is high in aromatase activity [1].
As a steroidal hormone, there is no transport protein needed to carry it across the plasma membrane.
Estrogen can freely pass through the plasma membrane and move into the nucleus where it can bind to its estrogen receptors and modify gene expression. Estrogen also regulates the reduction-oxidation (redox) state of the cell, altering mitochondrial function, and directly inhibits the activity of specific enzymes [2].
Estrogen secretion naturally varies in young women, increasing 10- to 100-fold over the menstrual cycle. Beyond estrogen, the menstrual cycle is characterized by significant changes in other important plasma hormones such as follicle stimulating hormone (FSH), luteinizing hormone (LH), and progesterone.
17β-estradiol levels rise from 5 pg/ml at the early follicular phase, to a peak of 200–500 pg/ml just before ovulation.
There is a rapid decrease in estradiol following ovulation which is followed by an increase in both estradiol and progesterone in the luteal phase giving a broad secondary peak. In order to prevent pregnancy, or simply to regulate hormone levels, many women take oral contraceptives that provide a daily low level of estrogen and progesterone. These pills typically maintain estradiol levels at ~25 pg/ml and decrease the ovulatory rise in estrogen [4]. In addition, this daily dose of estrogen and or progesterone also eliminates the cyclic rise in LH and FSH.
Figure: Hormonal fluctuation while taking an oral contraceptive (OC) containing both estrogen and progesterone [3]
In the absence of oral contraceptives, the menstrual cycle will occur from puberty until menopause when menses stop, FSH and LH rise, and plasma estradiol and progesterone concentrations remain constantly low.
Figure: Hormonal fluctuation in the years before and after menopause.
All musculoskeletal tissues including muscle, bone, ligament, and tendon have estrogen receptors. Within these tissues, estrogen is known to regulate metabolism, however, it is still unclear whether these effects are beneficial or harmful.
Consistent with a role for estrogen in regulating musculoskeletal function, menstruating women suffer more ACL ruptures than men, and menopause is characterized by increased risk of musculoskeletal injury, accelerated bone and muscle wasting, and decreased sensitivity to anabolic stimuli. To counteract many of the negative aspects of menopause, hormone replacement therapy (HRT) has been used to attenuate muscle and bone loss, and restore muscle protein balance [5].
Estrogen has several metabolic effects on skeletal muscle. When female animals lose estrogen through ovariectomy, mitochondrial function and membrane microviscosity decrease. The loss of estrogen also results in increased mitochondrial hydrogen peroxide production, decreased levels of antioxidant proteins such as glutathione peroxidase, and impaired insulin sensitivity. It is evident that these effects are due to the loss of estrogen since restoring normal estrogen levels restores cellular redox, and glucose homeostasis in
skeletal muscle [3, 6].
In addition to the metabolic roles, estrogen is clearly beneficial for muscle mass and strength [7].
Research indicates that 24 weeks of estrogen deficiency resulted in a 10% decrease in strength that corresponded with an 18% decrease in cross-sectional area of the muscle fiber [8]. Beyond the decrease in fiber cross-sectional area, ovariectomized rats do not recover as well following unloading. Supplementing the ovariectomized rats with estradiol was enough to return fiber cross-sectional area and injured fiber numbers to control levels. These data indicates that in the absence of estrogen, muscle is more prone to injury, and this limits regrowth [8].
Considering this research, it has been proposed that estrogen could stabilize the extracellular matrix or act as an antioxidant to decrease muscle injury [9].
In humans, much of the estrogen work has been performed in association with aging. Aging is a natural process that affects all aspects of life regardless of species. The goal of healthy aging is to slow the deterioration in physical and mental function as much as possible. One of the major changes with aging is the change in muscle protein turnover which is further affected by sex. In postmenopausal women, research indicates higher rates of muscle protein synthesis and breakdown when compared to age matched men and premenopausal women [5].
Even though higher rates of protein turnover might be expected to improve muscle quality, these women still experience a rapid decrease in muscle mass and strength, and as a result are more susceptible to age-related frailty [10].
Muscle mass is largely dependent on the balance between the synthesis and degradation of muscle protein.
The rapid decline in muscle mass following menopause essentially means either the increase in protein synthesis rate is counteracted by a greater increase in protein breakdown or that the proteins being synthesized are not the myofibrillar proteins but rather those needed for injury repair. Importantly, there is no significant sex difference observed in response to training and nutrition in middle-aged adults; however, postmenopausal women show reduced sensitivity to anabolic stimuli when compared to age-matched men [11].
This evidence indicates that a chronic decrease in estrogen attenuates the response to anabolic stimuli. In support of this evidence, when estrogen levels were raised to that of premenopausal women using estrogen replacement therapy, the response to anabolic stimuli was normalized [12].
These studies highlight the importance of estrogen in determining the sensitivity of muscle to anabolic signaling; however, more research is needed to understand whether monthly variations in estrogen have the same effect on anabolic signaling seen with chronic loss of estrogen. To date, evidence in this area indicates that, in young women the role of estrogen on muscle anabolism is still uncertain; however oral contraceptives with high progesterone have a negative impact on muscle [12].
Hormone replacement therapy has been recommended as therapeutic for postmenopausal women to counteract some of the negative aspects of menopause.
There was a very interesting, hallmark study in which habitual and maximal walking speed, thigh muscle composition, lower body muscle power (vertical jumping height), maximal isometric hand grip, and knee extension strengths were measured in 16 monozygotic twin pairs who were discordant for hormone replacement therapy use (one twin was on hormone replacement therapy while the other was not). Maximal walking speed and vertical jump height, thigh muscle cross-sectional area, and relative muscle area were larger in the hormone replacement therapy twins than their sisters. In addition, there was also a higher percentage of fat within the quadriceps muscle in the control group compared to the hormone replacement therapy and exercise + hormone replacement therapy groups [13].
Interestingly, exercise alone was less effective than hormone replacement therapy at maintaining muscle mass and function in these women. Together, these data suggest that hormone replacement therapy is beneficial for postmenopausal muscle mass and function, but that hormone replacement therapy together with exercise improves muscle mass and function more than either hormone replacement therapy or exercise alone. Altogether, the existing data suggest that acute treatment with estrogen does not improve basal muscle protein synthesis; however, estrogen increases the anabolic response to exercise and this may result in the increase in muscle mass reported in long term studies.
Since a ligament, such as the anterior cruciate ligament within the knee, shows a direct relationship between laxity and rupture, a stiffer ligament is preferred to maintain joint stability and prevent injuries. Due to its role in connecting a compliant muscle to a stiff bone, a stiffer tendon is not always beneficial. In terms of performance, a stiff tendon transmits the force produced by a muscle to the bone faster and this can improve performance.
However, when a tendon becomes too stiff this produces a strain concentration in muscle. Essentially, this means is that more of the strain (stretch) produced in a given movement is concentrated in the muscle that is connected to a stiff tendon than a muscle attached to a compliant tendon.
In other words, instead of the tendon stretching while the muscle contracts isometrically, a stiff tendon does not stretch, and the muscle is forced to lengthen while contracting. In effect, a muscle attached to a stiff tendon will experience more eccentric load for a given movement. We know that
eccentric movements produce more muscle injury than concentric or isometric movements [3].
This means that muscles attached to stiff tendons will suffer more injury for a given movement than those attached to compliant tendons. Therefore, stiff ligaments are always better, stiff tendons can improve performance, but if the tendon becomes too stiff the associated muscle will suffer more injuries.
Interestingly, women suffer fewer muscle injuries, and more ligament ruptures than men [14].
These observations are consistent with lower sinew stiffness in women than men. Since knee laxity changes with estrogen levels through the menstrual cycle, estrogen is believed to decrease sinew stiffness. The section below will address how estrogen affects sinew mechanics and adaptation to loading.
One of the best characterized musculoskeletal differences between men and women, is the rupture rate of the anterior cruciate ligament (ACL). ACL ruptures occur 2–8 times more often among female athletes than their male counterparts [15].
Given that there is a correlation between ACL injuries and knee laxity, and an association between knee laxity and the menstrual cycle, many studies investigated the relationship between ACL injuries and phase of the menstrual cycle. In general, research indicates a higher risk of ACL injury during the pre-ovulatory and ovulatory phases than luteal or follicular phases of the menstrual cycle [3].
Evidence shows that women knee laxity is dependent on female hormones and increases in direct relation to elevations in plasma estradiol levels. The variations in laxity were found to be cyclic in nature. When estrogen concentration increased during the menstrual cycle, knee laxity increased as well. Research also demonstrates that for every 1.3 mm increase in knee displacement, risk of ACL injury goes up 4-fold which could explain the 2- to 8-fold higher rate of ACL rupture in women [3].
Figure: Relationship between estrogen and ACL rupture in a normal cycle. The rate of anterior cruciate ligament (ACL) rupture in relation to female hormones throughout a standard menstrual cycle. Note that with the ovulatory rise in estrogen there is a concomitant rise in ACL ruptures. Adapted from Wojtys et al. (2002).[16]
Since knee laxity changes with cycle phase, many active women want to know whether oral contraceptives could prevent the change in laxity and injury risk. In support of this idea, research demonstrates that young women (aged 15–19) who undergo surgical repair of the ACL are 18% less likely to use oral contraceptives than matched controls [17].
In addition, an important study found a 20% higher relative risk value of ACL injury in women who had never used oral contraceptives than in women who were long-term users [18]. Together, these data suggest that ACL laxity changes through the cycle and eliminating the changes in estrogen using oral contraceptives decreases the risk of ACL rupture.
Due to the confusing data on the role of estrogen in musculoskeletal function, the question many active women have is “How do I best maximize musculoskeletal function based on the current level of research?” From the data discussed above, it appears that like many other performance strategies, hormonal cycling in young women is something that needs to be handled differently depending on the phase of training. Normal cycling is beneficial for musculoskeletal health, and performance for young women not competing in high level athletics.
In this population, the benefits of high estrogen on the anabolic response to exercise in muscle and tendon and improved muscle repair means that over time these women will have stronger muscles, tendons, and bones if they allow for the periodic rise of estrogen that occurs before ovulation.
In competitive athletes, the benefits of normal cycling can be seen by contrasting them with those athletes who experience relative energy deficiency in sport, formerly known as the female athlete triad. With a chronic energy deficiency, women stop normal cycling, and estrogen levels drop to very low levels, resulting in amenorrhea, loss of bone mass, and increased risk of musculoskeletal injury [19].
Due to the beneficial effects on muscle, tendon, and bone, competitive athletes should look to maintain their normal cycling when they are looking to maximize their adaptation to training: during the offseason or in the base phase of their training. As they begin to shift into the season, or during the specific preparation phase of training, they should consider taking an oral contraceptive that contains low levels of progesterone. The lower, steady state level of estrogen in the oral contraceptive would decrease the negative effects of the ovulatory rise in estrogen on tendon and ligament mechanics [2].
In this way, training would be performed in the absence of oral contraceptives and therefore lower tendon stiffness, and induce higher anabolic responses to training and maximal muscle repair on hard days. This would result in fewer muscle pulls and a greater metabolic cost of training, increasing the stimulus for adaptation and the likelihood of a healthy build up phase. Shifting to the low progesterone oral contraceptive in the specific preparation phase, or in season, would help increase stiffness within tendon and ligament while not preventing muscle repair following quality sessions or games. The result would be high rate of force development resulting in better performance and a lower risk of musculoskeletal injuries during the competitive season.
One important caveat is that this strategy would leave the athlete at a greater risk for catastrophic injury for ~5 days a month during training. Therefore, novel strategies to prevent the negative effects of estrogen on joint laxity are desperately needed to decrease the risk of catastrophic injuries in active women.
In postmenopausal women, the strategy is less clear.
In this population, hormone replacement improves muscle mass and function by improving muscle repair, and the anabolic response to feeding and exercise. Bone mass and function is also improved by hormone replacement therapy [20].
The issue is that long term hormone replacement therapy use is associated with decreased tendon cross-sectional area, especially in an active population. This may potentially result in a bigger, stronger muscle pulling on a small brittle tendon that is in turn connected to a stiffer bone. Ultimately, this can produce strain concentrations and promote injury. However, not taking hormone replacement therapy would accelerate
sarcopenia (skeletal muscle loss) and osteoporosis (bone loss).
Currently, the research indicates that hormone replacement therapy is beneficial for musculoskeletal function in postmenopausal women, but extra care should be taken to maximize tendon function. The gap in knowledge that needs to be investigated in the future is how women can get the positive effects of estrogen on muscle and bone repair and anabolic responses to loading and nutrition without the negative long-term effects on tendon. Phytoestrogens may provide some hope, but much further work is needed to establish the efficacy of these natural products.
It is clear from the evidence to date that estrogen has a dramatic effect on musculoskeletal function. Historically, a lot of research efforts were focused on the strong connection between estrogen and bone. However, recently the effect of estrogen on other musculoskeletal tissues such as muscle, tendon, and ligament has developed into a primary area of investigation. These studies make it clear that estrogen improves muscle proteostasis and increases sinew collagen content; however, the benefits on bone, and muscle come at the cost of decreased connective tissue stiffness.
However, as more women participate in sports; it is evident that these physiological effects of estrogen influence the decrease in power and performance and make women more predisposed to catastrophic ligament injury. In order to promote female participation in an active lifestyle throughout their life span, more research is needed to determine how nutrition, training, and
hormonal manipulation can be used to promote optimal performance at any age.
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