Relaxin
Relaxin is a protein hormone of about 6000 Da first described in 1926 by Frederick Hisaw.
The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 peptides of high structural but low sequence similarity; relaxin-1, 2 and 3, and the insulin-like peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, INSL6 remain uncharacterised.
Synthesis
In the female, it 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 disulfide bridges, and it appears related to insulin.Relaxin is produced from its prohormone, "prorelaxin", by splitting off one additional peptide chain reaction.
Function
In humans
In females, relaxin is produced mainly by the corpus luteum, in both pregnant and nonpregnant females. Relaxin levels rise to a peak within approximately 14 days of ovulation, and then decline in the absence of pregnancy, resulting in menstruation. 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. Relaxin's peak is reached during the first trimester and at delivery. Relaxin mediates the hemodynamic changes that occur during pregnancy, such as increased cardiac output, increased renal blood flow, and increased arterial compliance. It also relaxes other pelvic ligaments. It is believed to soften the pubic symphysis.In males, relaxin enhances motility of sperm in semen.
In the cardiovascular system, relaxin works mainly by activating the nitric oxide pathway. Other mechanisms include activation of NFκB leading to vascular endothelial growth factor and matrix metalloproteinases transcription.
Relaxin has been shown to relax vascular smooth muscle cells and increase nitric oxide production in rat endothelial cells, thus playing a role in regulation of cardiovascular function by dilating systemic resistance arteries. Relaxin increases the rate and force of cardiac contraction in rat models. Via upregulation of VEGF, relaxin plays a key role in blood vessel formation during pregnancy, tumour development or ischaemic wounds.
In other animals
In animals, relaxin widens the pubic bone and facilitates labor; it also softens the cervix, and relaxes the uterine musculature. Thus, for a long time, relaxin was looked at as a pregnancy hormone. However, its significance may reach much further. Relaxin may affect collagen metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing matrix metalloproteinases. It also enhances angiogenesis and is a potent renal vasodilator.In the mouse model, relaxin has been found to promote maturation of cardiomyocytes.
Several animal studies have found relaxin to have a cardioprotective function against ischaemia and reperfusion injury, by reducing cellular damage, via anti-apoptotic and anti-inflammatory effects. Relaxin has been shown to reduce cardiac fibrosis in animal models by inhibiting cardiac fibroblasts secreting collagen and stimulating matrix metalloproteinase.
In the European rabbit, relaxin is associated with squamous differentiation and is expressed in tracheobronchial epithelial cells as opposed to being involved with reproduction.
In horses, 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. Furthermore, granular and theca cells in the follicles will express relaxin in increasing levels depending on their size. During early pregnancy, the preimplantation conceptus will express relaxin, which will promote angiogenesis in the endometrium by up-regulating VEGF. 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.
In addition to relaxin production by the horse embryo, the maternal placenta is the main source of relaxin production, whereas in most animals the main source of relaxin is the corpus luteum. Placental trophoblast cells produce relaxin, however, the size of the placenta does not determine the level of relaxin production. This is seen because different breeds of horses show different relaxin levels. 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. During labour, there is a spike in relaxin 3–4 hours before delivery, which is involved in myometrial relaxation and softening of the pelvic ligaments to aid preparation of the birth canal for the delivery of the horse foetus. Following birth, the levels of relaxin will gradually decrease if the placenta is also delivered, however, if the placenta is retained in the mare then the levels will remain high. In addition, if the mare undergoes an abortion then the relaxin levels will decline as the placenta ceases to function.
Receptors
Relaxin interacts with the relaxin receptor LGR7 and LGR8, 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 menstrural cycle, suggesting that relaxin levels could play a role in abnormal uterine bleeding. However, more research needs to go into this 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.
Specific disorders related to relaxin have not been heavily described, yet a link to scleroderma and fibromyalgia has also been suggested.
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
A recombinant form of human relaxin-2 has been developed as investigational drug RLX030.It is suggested that relaxin could be used as a therapeutic target when it comes to gynaecological disorders.