Bone health

Bone health is important in all athletes and is essential in athletic performance. There are multiple influences on bone health including both modifiable and nonmodifiable risk factors. Hormone health and optimization plays a crucial role in supporting bone health. In the transgender population, hormone therapy may cause alterations in bone health and it is imperative that a provider treating this population understand potential effects.

It is important to consider the effects of using GnRHa such as leuprolide, not only in the general transgender population but also in the transgender athlete. During puberty, the rise of sex hormones contributes to bone mass development and by the age of 18 years old approximately 90% of peak bone mass is achieved [ ]. The use of GNRHa delays bone mineralization and the closing of epiphyses. It has been observed that the use of pubertal suppression in transgender adolescents has been shown to decrease in growth velocity and height, compared to natal sex counterparts [ , ]. It is unclear if arresting the pubertal process with a GNRHa may have long term side effects in the transgender population, including the possible increase in the incidence of fractures and osteoporosis. The long-term effects are not yet known.

Multiple studies have shown that trans females often begin the transition process with lower baseline BMD than trans males [ , ]. This is believed to be due to relative lower levels of physical activity in the trans female population. In a study by Schagen et al., 51 trans girls and 70 trans boys were found to have significantly decreased bone markers while on GNRHa. After the start of gender affirming hormone treatment, z -scores in trans boys normalized, whereas z -scores of trans girls remained below the population mean [ ]. A study by Klink et al. demonstrated similar decrease in z -score in trans girls from 0.8 to −1.4, whereas in trans males, there was a decrease between 0.2 and −0.3 further suggesting that use of GNRHa may lead to permanent lower BMD in this population, particularly trans females [ ]. In a study by Vlot et al., 34 trans males and 22 trans females demonstrated decreased z -scores over 2 years of GNRHa, although the overall fracture risk after 12 months was not determined [ ]. It should also be considered that most of these effects on bone mineral density have been observed before the use of cross-sex hormone therapy and some studies suggest the effects of cross-sex hormone therapy appears to restore BMD to natal sex counterpart levels while another study suggests partial normalization of levels [ , ]. It is recommended that transgender patient on GNRHa have DEXA scans at the start of GNRHa and every 2 years during treatment to monitor changes in BMD [ ].

In addition to pubertal suppression, trans females may also be given antiandrogen medication such as spironolactone to further suppress the effects of testosterone on the body. Spironolactone has been used in the treatment of hyperaldosteronism and has been shown to reduce bone turnover markers in postmenopausal women with this condition [ ]. One may further infer mineralocorticoid receptor antagonist effects of spironolactone may enable resorption of calcium and thus reduce PTH levels, similar to the effects seen in other diuretics on bone health [ , ]. At this time, there are no studies that examine the clinical impact of spironolactone therapy on long-term bone health in the male to female transgender population.

Both estrogen and testosterone are crucial for the regulation of bone metabolism in both men and women. Estrogen acts on osteocytes, osteoblasts, and osteoclasts to decrease activation of bone remodeling and help preserve the maintenance of bone formation [ , ]. There is a positive correlation between estrogen levels and bone mineral density which has been studied extensively in postmenopausal women [ ]. For this reason, postmenopausal women are at high risk for developing osteoporosis as estrogen levels rapidly decline [ ]. It is important to monitor bone density as estrogen levels decline in trans men. After ovariectomy in trans men, which mimics menopause, BMD has been shown to be stable over 12 months, but decreases over the 28–63 months [ ]. In this same study, trans females studied demonstrated that estrogen therapy preserved BMD after testosterone deprivation with significant increase after 1 year, although BMD ultimately decreased to baseline after 28–63 months of treatment [ ].

Testosterone is also important in the maintenance of BMD. Testosterone acts on the IGF-1 and TGB-beta receptors in osteoblasts to promote bone formation. In addition to testosterone’s effects on the these receptors, testosterone is converted to estrogen via aromatase which further encourages bone formation. It has been observed in aging natal males and males on androgen reduction therapy, that BMD decreases as testosterone levels decrease. It is important to consider the changing both estrogen and testosterone levels in transgender athletes when assessing bone health [ ].

Clinical considerations of this data would suggest optimizing other forms of bone mineral formation such as screening for vitamin D deficiency, calcium and vitamin D supplementation, encouraging weight-bearing exercise, as well as limiting other risk factors for BMD loss such as smoking and alcohol use. In addition, the period between starting GnRHa and cross-sex hormone therapy lends itself to be a vulnerable time in terms of bone mineral density when epiphyseal fusion is arrested, but maintenance hormonal therapy has not yet started [ , ]. Threshold for stress fracture evaluation may be somewhat lower in a transgender person who has been on pubertal suppression therapy as they may have not reached peak BMD when this therapy is suspended.

Current guidelines for bone density screening in adult transgender people is similar to the same the general population, which includes screening at age 65, and younger if risk factors are present. Transgender people who have undergone gonadectomy without HRT for at least 5 years should be considered for screening [ ].

Additionally, excessive exercise and malnourishment can lead to the down regulation of the hypothalamus-pituitary axis leading to a functional hypothalamic amenorrhea in young active female or transgender athletes, significantly increasing their risk of stress fractures. Therefore, providers shoulder have a low threshold for fracture screening, particularly with endurance or weight class-dependent athletes or in the setting of even minimal trauma. Standardized z -scores used to assess BMD are age and gender matched values. It is unclear the relevance of these scores as the hormonal milieu of the patient changes. Providers should also be aware of hormonal medication access and compliance, as rapid changes or cessation of medication can have detrimental effects on bone health. It is important to remember that treating low BMD goes beyond simply providing oral or transdermal hormone therapy, and requires full assessment of training volume, nutritional intake, vitamin D and electrolyte levels, thyroid function tests, and psychological factors.

Muscle health

Muscle is the largest endocrine organ of the body. It plays an important role in metabolic regulation and support of the skeleton. The use of GAHT can have varying effects on both the structure of muscle tissue and its vulnerability to injury.

Testosterone leads to increased muscle mass, due to increase in muscles protein synthesis. This in turn leads to an increase in muscle fibers and size, muscle satellite cell numbers, numbers of myonuclei and size of motor neurons [ , ]. Additionally, testosterone increases skeletal muscle myostatin expression, mitochondrial biogenesis, myoglobin expression and IGF-1 content, which increases the energy and power generated by the skeletal muscle [ , ]. After the initiation of testosterone therapy, muscle mass and strength begins to increase at 6–12 months and can peak between 2 and 5 years [ ]. In trans males, this rapid rate of muscle growth is often occurring on a relatively smaller skeletal frames. In addition, testosterone has also been shown to increased the desire to compete and drive to exercise [ , ]. This increased desire to exercise and rapid muscle hypertrophy may lead to overuse injuries or other pathologies such as compartment syndrome and avulsion injuries [ ]. It is important for the sports medicine clinician to understand changes in exercise habits and length of testosterone treatment in order understand physique changes. Neurological and vascular examination along with timing of symptoms are important to assess for rhabdomyolysis and compartment syndrome in these settings. Conversely, testosterone may aide in muscle tissue repair. Preclinical studies have shown that an association between testosterone and muscle regeneration in the setting of injury, although there have not been any human clinical studies to confirm this finding [ ]. Use of exogenous testosterone has been used in the treatment of sarcopenia and improve rehabilitation outcomes in people with muscle loss including burn victims, the elderly, and undernourished people with stress fractures [ ]. In the transgender athlete population, exogenous testosterone may improve muscle injury recovery, whereas testosterone antagonism may prolong recovery. Further studies are needed to investigate these effects [ , ].

Estrogen plays a role in energy production, glucose regulation, strength preservation, and injury prevention in muscle tissue. At a cellular level, the absence of estrogen is associated with impaired mitochondrial function and insulin sensitivity, leading to overall decreased energy production and impaired glucose metabolism in skeletal muscle [ ]. Estrogen is also beneficial for muscle mass and strength as observed in animal models. In ovariectomized mice, loss of estrogen resulted in a 10% decrease in strength in addition to a decrease in muscle fiber cross-sectional area [ ]. In postmenopausal women, there is a rapid decline in muscle mass and decreased sensitivity to anabolic stimuli [ ]. When estrogen levels are raised to that of a premenopausal woman through estrogen replacement therapy (ERT), the response to anabolic stimuli was normalized [ ]. This demonstrates estrogen role in the maintenance of muscle mass and increased muscle growth potential through increasing the anabolic response to exercise [ ]. It has been suggested that estrogen supplementation reduces injury incidence, muscle inflammation, muscle damage, and improves recovery in postmenopausal women [ ]. Several studies show that estrogen therapy in trans females is associated with a decrease in muscle fiber cross-sectional area, lean body mass, and strength [ ]. In trans females the decrease in lean body mass and strength begins around 3–6 months of treatment and maximizes at 1–2 years. Despite this significant decrease, a recent study by Harper et al. demonstrated that at 36 months of GAHT, overall values of strength, LBM and muscle area remain higher when compared to natal females [ ]. It is unclear if there if injury incidence and recovery is altered in this population.

Beyond the physical changes occurring at the tissue level, there are also neuromuscular changes that may be occurring with hormone therapy. A study by Casey et al. demonstrated that at high estrogen phase of the menstrual cycle, the muscle stretch reflex of the rectus femoris was 2.4× lower than it is at other times of the cycle, suggesting possible hormonal influence on neuromuscular control. Further investigation of this finding may demonstrate changes in factors such as movement patterns and agility, which can effect sports performance and injury patterns [ ].

Tendon and ligament

Sex hormone receptors are present on tendon and ligaments which affect function and susceptibility to injury. The mechanical properties of both the tendon and ligament are dependent on collagen fiber density, diameter, orientation, and cross-linking. The fibers can be cross-linked in two ways: enzymatically and nonenzymatically [ ].

Although testosterone is known for its anabolic effect on muscles and bone it might have a paradoxical effect on tendons and ligaments. Testosterone receptors on tendon are responsible for the proliferation of tenocytes. Tenocytes are responsible for the formation and turnover of the extracellular matrix. Testosterone supplementation has been associated with increased incidence of tendon rupture, especially in the upper body tendons [ ]. This may be due to testosterone’s rate of hypertrophic effect on the muscle belly only, while tendon strength remains constant, this leading to increased force along the tendon, leading to rupture [ ]. In addition to the strength of tendon, it has been demonstrated that animals with increased testosterone exposure with exercise have had increased collagen turnover and dysplasia in tendons, leading to increased rigidity and rupture [ ]. In a study by Testa et al. that in a cohort of over 9000 natal male patients prescribed testosterone replacement therapy for at least 90 days were at 3.6 greater risk of sustaining a rotator cuff tendon tear [ ]. This finding may be due to the increase in collagen turnover, as well as other factors including increased physical activity and drive to exercise. All of these factors are important to consider when assessing injury risk in a transgender athlete on testosterone supplementation.

On the other hand, estrogen leads to increased tendon compliance, which is associated with fewer tendinous injuries [ ]. Estrogen directly inhibits lysyl oxidase, decreasing collagen cross-link formation and increasing tendon compliance [ ]. As a result, natal females have significantly lower rates of adductor and hamstring strains than men. In professional soccer, natal females suffer 54% fewer muscle strains than their male counterparts [ ]. Natal females are also at a markedly lower risk of achilles tendon rupture than natal males prior to menopause—whereas after menopause, the rates of achilles tendon rupture becomes similar in both sexes [ , ]. Thus, estrogen plays a key role in the prevention of tendinous injury prevention in natal female athletes. Estrogen increases both ligamentous and tendon laxity and compliance. While the increase in ligamentous laxity leading to increased flexibility, it may increase the likelihood of ligamentous injury. In fact, ACL ruptures occur 2 to 8 times more in female than male athletes [ ]. For every 1.3 mm increase of knee displacement through ligamentous laxity, the risk of an ACL injury increases fourfold [ ]. ACL injuries have also been shown to occur more often during the high estrogen phase of the menstrual cycle [ ]. Although there are multiple factors that may effect this injury rate beyond estrogen concentration including recovery, anatomy, training, and other endogenous hormones. In trans female athletes, exogenous estrogen may be protective against musculotendinous injury while at the same time, increasing ligamentous laxity. This may predispose trans females to ligamentous injury if they continue to use training and recovery regimens that were initiated prior to medical transition.