The Role of Relaxin in Normal and Abnormal Uterine Function During the Menstrual Cycle and Early Pregnancy

Abstract

The hormone relaxin is a 6-kDa peptide with high structural similarity to insulin. It is primarily produced by the corpus luteum during pregnancy but is also synthesized by other reproductive organs such as the uterus, decidua, and placenta. Relaxin binds to its receptor RXFP1, which has been localized to a wide variety of reproductive and nonreproductive tissues. The peptide's many uterotropic effects include stimulating uterine growth and vascularization, remodeling extracellular matrix components, and regulating vascular endothelial growth factor in preparation for implantation. Evidence also supports a role for relaxin in the systemic maternal vascular adaptations required for a healthy pregnancy. Diminished relaxin levels in early pregnancy are linked with increased risks of miscarriage and the development of preeclampsia. In addition to pregnancy, relaxin may also play a functional role in the uterus during the menstrual cycle, and modified relaxin activity may contribute to gynecological disorders such as uterine fibrosis and endometriosis. Despite over 75 years of research, we still have a limited understanding of relaxin's broad roles in the uterus, particularly as there are significant species differences in its synthesis and activity, which restricts the use of animal models for human-centric questions. Here, we review current knowledge regarding relaxin actions in the human uterus during the menstrual cycle and in early pregnancy, with a focus on its potential roles in various gynecological disorders, as well as the pregnancy disorders such as preeclampsia, recurrent miscarriage, and early pregnancy loss.

Optimal Paradigms for Measuring Peak Serum Relaxin in Eumenorrheic, Active Females

“…It is possible that there are some athletes who do not produce detectable levels of relaxin, but it is also possible that the limited sampling frequency (only two samples on post-ovulatory days 6 and 8) during one menstrual cycle may have missed the window for detectable concentrations of serum relaxin in some women. In support of the latter, two prior studies showed that relaxin peaks later in the menstrual cycle in the majority of women (days [10][11][12]. However, these studies were limited by small sample size and the physical activity status of these women is unknown [15,16].…”

“…As part of this larg-the brain [9]. Relaxin-2 is also present in non-pregnant women [10] and has been linked to changes in connective tissue resulting in altered mechanical properties of ligaments, tendons, muscle and cartilage [5,11]. How relaxin alters connective tissue properties is not fully understood, but proposed mechanisms, include:…”

Relaxin 2/RXFP1 Signaling Induces Cell Invasion via the β-Catenin Pathway in Endometrial Cancer

“…Relatively high levels of RXFP1 are reported in uterine tissue [9,10,11]. It is well-known that three peptide forms of RLN: RLN1, RLN2, and RLN3, exist in humans, although the roles of two of the peptides, RLN1 and RLN3, remain unclear [12]. RLN2, which is produced in male prostate tissue [13], and female corpus luteum tissue [14,15] is known as a major human circulating RLN [12,16].…”

Serum relaxin and cervical length for prediction of spontaneous preterm birth in second‐trimester symptomatic women

“…The placenta and decidua also produce relaxin, but this fraction has an autocrine or paracrine action rather than entering the circulation. In addition to its other functions related to maternal adaptation in normal pregnancy, relaxin has also been implicated in the process of labor, both term and preterm. However, the data regarding changes in relaxin levels in preterm labor are conflicting.…”