Estrogen and testosterone supplementation improves tendon healing and functional recovery after rotator cuff repair

Abstract

Failure of healing after rotator cuff repair (RCR) is common. The purpose of the current study was to evaluate the effect of systemic estrogen or testosterone supplementation on tendon healing after RCR. Seventy‐two adult male mice were utilized for all experiments. The supraspinatus tendon was transected and repaired with 6‐0 Prolene suture on the left shoulder of 51 animals. Mice were segregated into three groups postoperative: (1) vehicle group (VG; n = 18), (2) estrogen group (EST; n = 17), and (3) testosterone group (TST; n = 16). An unrepaired control group (unrepaired, n = 21) did not have surgery. Utilizing these animals, histological analysis, activity testing, biomechanical testing and RNA sequencing (RNA‐seq) was performed. At 8 weeks post‐RCR, TST, and EST supplementation improved the overall histologic structure of the repaired enthesis site. No differences in ultimate failure loads or stiffness were detected between VG, EST, and TST groups after biomechanical testing. RCR caused a reduction in wheel activity compared to unrepaired controls and supplementation with TST restored wheel activity. RNA‐seq analysis indicated that estrogen and testosterone regulated different pathways associated with enthesis healing, including a suppression of inflammatory signaling. Supplementation with sex hormones improved the structure of the repaired tendon enthesis and significantly regulated expression of diverse pathways regulating multiple biological processes. Testosterone administration following RCR restored wheel activity without having a detrimental impact on biomechanical strength. Future human studies of sex hormone supplementation after RCR are warranted as supplementation in an animal model may improve tendon enthesis healing.

Functional Changes to Achilles Tendon and Enthesis in a Mouse Model of an Adolescent Masculine Gender-Affirming Hormone Treatment

“…In tendon, the effects of estrogen and T have recently been reported to have similar effects but have differing mechanistic targets during healing (19). RNA sequencing perfomed on the supraspinatus tendon 2 weeks post laceration suggested these hormones can mediate gene expression during the healing process (19). These considerations for the differences between sex hormones and the impact on tendon health are important for transgender and gender diverse youth who may use GnRHa to delay or inhibit secondary sex characteristics.…”

“…The potential effects of pubertal suppression on the functional properties of musculoskeletal tissues, like tendon, is an important and understudied topic. In tendon, the effects of estrogen and T have recently been reported to have similar effects but have differing mechanistic targets during healing (19). RNA sequencing perfomed on the supraspinatus tendon 2 weeks post laceration suggested these hormones can mediate gene expression during the healing process (19).…”

17β-Estradiol Effects in Skeletal Muscle: A 31P MR Spectroscopic Imaging (MRSI) Study of Young Females during Early Follicular (EF) and Peri-Ovulation (PO) Phases

“…During or before menstruation, when blood estrogen levels decrease, many women frequently experience increased fatigue and diminished energy levels [6,7]. Additionally, estrogen deficiency, often seen in menopausal women, has been linked to a range of musculoskeletal and neuromuscular disorders, such as sarcopenia, 2 of 16 osteoporosis, frailty, obesity, dementia, atherosclerosis, metabolic syndrome, and type 2 diabetes, with reported benefits when endogenous estrogen levels rise or exogenous estrogen is supplemented [2,[8][9][10][11][12][13][14][15][16].…”