The cause of developmental dysplasia of the hip is still debated, although ligamentous laxity is a contributing factor [1]. Few studies have found evidence for a hormonal effect on DDH. Only a few studies have found an association between DDH and serum or cord blood relaxin concentrations, and many others have found no association. However, our study appears to be the only one that measured relaxin receptors in the ligament of head of femur [16].
Relaxin acts on the extracellular matrix through metalloproteinases by enhancing collagen degredation [8]. Relaxin is associated with both local and generalized laxity [17]. In patients with laxity-associated arthrosis of the first carpometacarpal joint, the concentration of relaxin inhibitors was higher in the volar oblique and anterior oblique ligaments, indicating that relaxin was involved as a cause of laxity [18, 19]. Another study in healthy humans found that trapezial-metacarpal joint laxity was proportional to serum relaxin concentrations [17]. A study in rats found that recombinant human relaxin 30 ng/mL weakened the joint capsule and decreased collagen accumulation in a dose-dependent way [20].
In women athletes, the “monthly window of potential injury” has been associated with hormonal changes, as defined by Möller-Nielsen [21]. This window coincided with peak concentrations of relaxin during the menstrual cycle, and generalized joint laxity was increased during these peak times [21]. Relaxin also increased ligamentous laxity during pregnancy [22]. Relaxin receptors are up-regulated by estrogen therapy, and joint laxity occurring after the first trimester of pregnancy is synchronous with peak relaxin contrations [22].
Steinetz et al. hypothesized that increased serum relaxin concentration may result in increased joint laxity. In their study, they reported that increased levels of relaxin in pregnant woman with pelvic join instability or hip joint laxity compared with the control group. (Y) 3 years later Dragoo et al. reported that increased level of serum relaxin resulted in reduced ligament integrity and increased risk of injury for anterior cruciate ligament (ACL) (Y-1)
In one of two other separate studies by Dragoo, tibial translation in guinea pigs was increased by 12.8% (absolute increase, 1.09 mm) 21 days after relaxin administration. The maximum load of the anterior cruciate ligament was also weaker by 36%, dropping from 64.1 N to 40.4 N, and relaxin altered the structure of the ligament by collagenolytic effects [23]. In the second study, relaxin increased the synthesis of collagenase and many matrix metalloproteinases in anterior cruciate ligament rupture and decreased local collagen synthesis in women orthopedic patients [24]. Increases in estrogen and relaxin during the normal menstrual cycle last only a very short time and are insufficient to explain any collagenolytic effect. It appears that long-term fluctuations are required to remodel the collagen [24].
Prolidase activity is increased in patients with DDH [25]. High prolidase activity indicates increased collagen metabolism, which is consistent with relaxin's mechanism of action. In the present study, we found that the number of relaxin receptors was twice as high in infants with DDH than in the elderly control group. We believe that this higher number of receptors and long-term exposure to relaxin from the mother during pregnancy may alter the nature of the ligamentum teres, resulting in hyperlaxity, possibly predisposing the fetus to DDH. However, in this case, it appears that the higher number of fetal receptors, rather than the concentration of relaxin from the mother, might be the cause because Forst et al. found that relaxin concentrations in specimens from cord blood were lower in neonates with DDH than in those of a healthy control group [4]. In a similar study, Vogel et al. also found no relationship between relaxin concentrations and DDH in 15 infants with DDH [26].
The ligamentum teres is important in stabilizing the pathophysiology of DDH [27]. Wenger et al. suggested that the strength of the ligamentum teres was crucial in the biomechanics of the hip and recommended surgical reconstruction for patients with DDH [27]. Another study on rats reported that greater strength of the ligamentum teres helps proper remodeling of the acetabulum against the femoral head [28].
The risk of DDH is four times as high in females as in males [29]. Desteli et al. found a negative relationship between the number of estrogen receptors and collagen metabolism in the ligamentum teres harvested from infants with DDH [30]. Furthermore, relaxin receptor isoforms are down-regulated with progesterone and high-dose estrogen, increasing the laxity, whereas progesterone and estrogen are down-regulated with testosterone [31]. Testosterone concentrations are 8 times as high in men as they are in women, and testosterone reduces the expression of the relaxin receptor, as well as decreasing the passive range of motion in joints [32].
The following questions arise from these findings: because relaxin is a maternal hormone, is it likely that attenuated relaxin activity improves a hip from Graf type IIa to type I in neonates? In addition, in hips with more relaxin receptors, although relaxin concentrations are reduced in time, does the long-term action of relaxin cause permanent dysplasia? Finally, can the down-regulation of relaxin receptors caused by testosterone in men be the reason for their lower rate of DDH? All these questions may guide future studies. In this preliminary study, we used a single evaluator to score the intensity of staining. Given that we found an association between relaxin receptors and DDH, however, future studies should reduce the chances of bias by using two or more evaluators.