Do Relaxin Levels Impact Hip Injury Incidence in Women? A Scoping Review

Abstract

Purpose: The aim of this review is to assess the current evidence regarding the impact of relaxin on incidence of soft tissue hip injuries in women.

Methods: A trained research librarian assisted with searches of PubMed, Embase, CINAHL, and SPORTDiscus, with a preset English language filter. The review was completed per the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis methodology. Included studies required assessment of relaxin effects on musculoskeletal health, pelvic girdle stability, or hip joint structures in human subjects. Letters, texts, and opinion papers were excluded.

Results: Our screen yielded 82 studies. Molecularly, relaxin activates matrix metalloproteinases (MMPs) including collagenases MMP-1/-13 and gelatinases MMP-2/-9 to loosen pelvic ligaments for parturition. However, relaxin receptors have also been detected in female periarticular tissues, such as the anterior cruciate ligament, which tears significantly more often during the menstrual cycle peak of relaxin. Recently, high concentrations of relaxin-activated MMP-9 receptors have been found on the acetabular labrum; their expression upregulated by estrogen.

Conclusions: Menstrual cycle peaks of relaxin activate MMPs, which locally degrade collagen and gelatine. Women have relaxin receptors in multiple joints including the hip and knee, and increased relaxin correlates with increased musculoskeletal injuries. Relaxin has paracrine effects in the female pelvis on ligaments adjacent to hip structures, such as acetabular labral cells which express high levels of relaxin-targeted MMPs. Therefore, it is imperative to investigate the effect of relaxin on the hip to determine if increased levels of relaxin are associated with an increased risk of acetabular labral tears.

Keywords: female reproductive cycle; hip preservation; hormonal contraceptives; menstrual cycle hormones; relaxin; sex differences; sex-based.

Figure 1

Menstrual cycle hormone peaks, molecular effects. The sequence of hormone peaks for ovulatory cycles. Estrogen levels peak first, increasing expression of relaxin receptors in the body and increasing global synthesis of MMPs. The drop in estrogen triggers ovulation, and the remains of that ovarian follicle from the corpus luteum. As a temporary endocrine body, the corpus luteum secretes progesterone to prepare the endometrium for pregnancy and to sustain itself. It also synthesizes and relaxin, which binds receptors and activates. MMPs recently upregulated by estrogen while suppressing de novo collagen synthesis. Relaxin is active during the luteal phase, chiefly CD21-24.

Figure 2

The dual functions of relaxin in target tissues. The two main mechanistic pathways by which relaxin decreases tissue quality and quantity of collagen after binding to its receptor. Upon binding relaxin receptors in target tissue, two processes impacting collagen proceed concurrently. Above, left-relaxin increases production of all MMPs, but particularly the collagenases and gelatinases capable of digesting ECM components. Thus one mechanistic pathway detrimental to target tissue collagen is the degradation of existing collagen by these. MMPs. Above, right-relaxin also suppresses function of/differentiation into myofibroblasts. These cell secrete multiple ECM components and modulate ECM cross-linkage, allowing relaxin to impair de novo collagen synthesis is target tissue.

Figure 3

Hypothesized mechanism of relaxin-induced acetabular labrum damage. Known factors giving rise to hypothetical impact of relaxin on the acetabular labrum. It is known that MMP-9 is the inducible gelatinase (MMP-2 is not) which is expressed at high levels during the luteal phase for endometrial. It is known that relaxin, produced in the pelvis and exerting paracrine effects, increases MMP-9 expression. Finally, it is known that the anchored to the pelvis serves as a "seal" enclosing synovial fluid, which may contain hormones, and that the cells express MMP-9 at an unusually high level when induced . Given these known factors: the acetabular labrum likely expresses RXFPs and increases MMP-9 expression in a paracrine to relaxin. MMP-9 degrades ECM proteins, weakening the labrum.