Relaxin

In the female, relaxin is produced by the corpus luteum of the ovary, the breast and, during pregnancy, also by the placenta, chorion, and decidua. In the male, it is produced in the prostate and is present in human semen. == Structure ==

Structurally, relaxin is a heterodimer of two peptide chains of 24 and 29 amino acids linked by three disulfide bridges, and it appears related to insulin. Relaxin is produced from its prohormone, "prorelaxin", by post-translational proteolytic cleavage of its signal peptide and C domain peptide. == Function in humans ==

Reproduction In females, relaxin is produced mainly by the corpus luteum, in both pregnant and nonpregnant females. Relaxin may be involved in the vital process of decidualisation, working alongside steroid hormones to allow the endometrium to prepare for implantation. During the first trimester of pregnancy, levels rise and additional relaxin is produced by the decidua. Blood plasma levels of relaxin peak during the first trimester (8-12 weeks) at 1.2 ng/mL and subsequently drop following demise of the corpus luteum. In pregnancy, relaxin mediates the hemodynamic changes that occur such as increased cardiac output and increased renal blood flow. Relaxin is believed to relax the uterine muscle and to loosen the ligaments holding the pelvic bones together, in order to prepare the birth canal for the birth. It may cause a woman to feel that other ligaments are looser, such as in the shoulders, knees, hips, and ankles. In males, relaxin enhances motility of sperm in semen. Also, relaxin is found in higher than normal concentrations in the ejaculate of men who were born without their vas deferens and seminal vesicles. Cardiovascular function In the cardiovascular system, relaxin is secreted by the heart and functions as a vasodilator mainly through the nitric oxide pathway. Other mechanisms include activation of NFκB leading to vascular endothelial growth factor (VEGF), activation of PI3K/Akt-associated signaling pathways, and matrix metalloproteinases transcription. In ex vivo experiments using subcutaneous resistance arteries, relaxin has shown to be a powerful endothelium-dependent vasodilator. == Function in other animals ==

Reproduction In animals, relaxin widens the pubic bone and facilitates labor; it also softens the cervix (cervical ripening), and softens the pubic symphysis in rat and guinea pig models. It also enhances angiogenesis and is a potent renal vasodilator. In horses (Equus caballus), relaxin is also an important hormone involved in pregnancy; however, before pregnancy occurs, relaxin is expressed by ovarian structures during the oestrous cycle. Prior to ovulation, relaxin will be produced by ovarian stromal cells, which will promote secretion of gelatinases and tissue inhibitors of metalloproteinases. These enzymes will then aid the process of ovulation, which will lead to the release of a developed follicle into the fallopian tube. This will allow the endometrium to prepare for implantation. In horses alone, the embryo in the uterus will express relaxin mRNA at least 8 days after ovulation. Then as the conceptus develops expression will increase, which is likely to promote embryo development. From 80 day of gestation onwards, relaxin levels will increase in the mare's serum with levels peaking in late gestation. Moreover, the pattern of relaxin expression will follow the expression of oestrogen, however, there is not yet a known link between these two hormones. ==Receptors==

Relaxin interacts with the relaxin receptor LGR7 (RXFP1) and LGR8 (RXFP2), which belong to the G protein-coupled receptor superfamily. They contain a heptahelical transmembrane domain and a large glycosylated ectodomain, distantly related to the receptors for the glycoproteohormones, such as the LH-receptor or FSH-receptor. Relaxin receptors have been found in the heart, smooth muscle, the connective tissue, and central and autonomous nervous system. ==Disorders==

Women who have been on relaxin treatment during unrelated clinical trials have experienced heavier bleeding during their menstrual cycle, suggesting that relaxin levels could play a role in abnormal uterine bleeding. However, more research is needed to confirm relaxin as a direct cause. A lower expression of relaxin has been found amongst women who have endometriosis. The research in this area is limited and more studying of relaxin's contribution could contribute greatly to the understanding of endometriosis. Pregnancy It is possible that relaxin in the placenta could be a contributing factor to inducing labour in humans and therefore serum relaxin levels during pregnancy have been linked to premature birth. ==Pharmacological targets==

Recombinant forms of human relaxin-2 such as volenrelaxin (LY3540378) and serelaxin (RLX030) have been developed as investigational drugs. It is suggested that relaxin could be used as a therapeutic target when it comes to gynaecological disorders. == Evolution ==

Relaxin 1 and relaxin 2 arose from the duplication of a proto-RLN gene between 44.2 and 29.6 million years ago in the last common ancestor of catarrhine primates. The duplication that led to RLN1 and RLN2 is thought to have been a result of positive selection and convergent evolution at the nucleotide level between the relaxin gene in New World monkeys and the RLN1 gene in apes. As a result, Old World monkeys, a group that includes the subfamilies colobines and cercopithecines, have lost the RLN1 paralog, but apes have retained both the RLN1 and the RLN2 genes. == See also ==