In support, Chen et al. (2014) found an estrogen dose-dependent increase in proliferation of cells from the ligamentum flavum that lasted only 24 h in culture (Chen et al., 2014). 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. Further, Rahr-Wagner et al. found a 20% higher relative risk (RR) value of ACL injury in women who had never used OCs than in women who were long-term users (Rahr-Wagner et al., 2014). The resulting studies in general find a higher risk of ACL injury during the pre-ovulatory and ovulatory phases than luteal or follicular phases of the menstrual cycle (Beynnon et al., 2006; Ruedl et al., 2009; Lefevre et al., 2013). Interestingly, women suffer fewer muscle injuries, and more ligament ruptures than men (Arendt and Dick, 1995; Sewright et al., 2008; Hägglund et al., 2009; Edouard et al., 2016; Leblanc et al., 2017). In a cross-sectional analysis of 840 postmenopausal women (259 on ERT and 581 controls), Taaffe et al. (2005) found that muscle cross-sectional area (CSA) and grip strength were greater in ERT users than in non-users (Taaffe et al., 2005). Interestingly, exercise alone was less effective than HRT at maintaining muscle mass and function in these women. There was also a higher percentage of fat within the quadriceps muscle in the control group compared to the HRT and ExHRT groups (Sipilä et al., 2001). A similar but smaller increase in vertical jump height (6.8%) and muscle CSA (6.3%) was observed in the HRT group. Additional preclinical and clinical studies will be needed to better define how testosterone and AASs modulate muscle regeneration and the dose and duration for which they should be given for potential clinical benefit. Conversely, two other preclinical studies found that ND administration was able to increase muscle regeneration, which was evaluated based on the number and morphology of myofibers present.97,98 In a rodent model of muscle contusion, Beiner et al.96 found that ND administration did not increase the force-producing capacity of the gastrocnemius at 7 or 14 days postinjury. This process is essential for tendon-to-bone healing and ligament recovery. Oestrogen helps preserve muscle mass and supports collagen creation. In the presence of relaxin, knee ROM in the control group was significantly higher than in the testosterone-treated group. An understanding of the testosterone effect on joint laxity is currently not fully understood. Serum relaxin level fluctuates throughout the reproductive cycle and is markedly increased during pregnancy . The patellar tendon, which connects patella to tibia tuberosity stabilizes the patella and also prevents knee hyperextension . Medial and lateral collateral ligaments (MCL and LCL) prevent excessive varus-valgus-forces while anterior cruciate ligament (ACL) prevents knee hyperextension . Recently, a case of spontaneous rupture of the long head of the biceps tendon in a woman with hypothyroidism has been reported14. Studies were deemed relevant if they were published in English and contained original research providing relevant knowledge related to the correlation between hormones and tendons, were selected8. The interest in understanding their mechanism of action strives in developing therapeutic strategies for pathologic tendon conditions. The frequent association between human tendinopathies and endocrine disorders, as well as experimental data, suggest that also hormones are involved in modifying tendon homeostasis6,7. It has been shown that adverse metabolic situations (diabetes1,2, obesity3 and hypercholesterolemia4) may alter the normal tendon response, and favor early degeneration5. The biological milieu surrounding the tendon components strongly influences the reaction to loading. This finding suggested that knee was not responsive to relaxin in the presence of testosterone due to relaxin receptor downregulation. Our study has provided the first direct evidence on testosterone effect on the passive ROM in rats’ knee. A positive correlation between plasma testosterone, free androgen index (FAI) and anterior cruciate ligament stiffness has been reported in young females near ovulation . The PINP data suggests that women synthesize more collagen in response to exercise; however, this collagen may not be incorporated into the tendon to the same degree in women. This is in contrast to men where the same 1 h kicking exercise increased new collagen incorporation 70% by 24 h (Miller et al., 2005). In the first of these studies, a group taking oral contraceptives containing moderate estradiol was compared to non-OC users in the follicular phase, when estrogen levels are naturally low, both at rest and following 1 h of kicking exercise. In fact, women are at lower risk of sustaining an Achilles' tendon rupture than men until menopause, after which the risk becomes similar in both sexes (Hansen and Kjaer, 2014, 2016). Note that even though there is a slight rise in collagen, the stiffness of the grafts decreases concomitant with an increase in estrogen in the media. In these experiments, treating engineered ligaments with physiologically high estrogen for 48 h resulted in an 80% decrease in lysyl oxidase activity without changing LOX expression (Figure 3). Although expression of collagen mRNA didn't change significantly, there was a decrease in the ratio of collagen to elastin at the protein level after the cells were treated with 17β-estradiol.
