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.{{cite journal | vauthors = MacLennan AH | title = The role of the hormone relaxin in human reproduction and pelvic girdle relaxation | journal = Scandinavian Journal of Rheumatology. Supplement | volume = 88 | pages = 7–15 | year = 1991 | pmid = 2011710 }}

{{See also|Insulin/IGF/Relaxin family}}

Structurally, relaxin is a heterodimer of two peptide chains of 24 and 29 amino acids linked by three{{cite journal |last1=Haugaard-Kedström |first1=Linda M. |last2=Hossain |first2=Mohammed Akhter |last3=Daly |first3=Norelle L. |last4=Bathgate |first4=Ross A. D. |last5=Rinderknecht |first5=Ernst |last6=Wade |first6=John D. |last7=Craik |first7=David J. |last8=Rosengren |first8=K. Johan |title=Solution Structure, Aggregation Behavior, and Flexibility of Human Relaxin-2 |journal=ACS Chemical Biology |date=20 March 2015 |volume=10 |issue=3 |pages=891–900 |doi=10.1021/cb500918v |pmid=25547165 |url=https://pubs.acs.org/doi/10.1021/cb500918v |access-date=22 January 2023|url-access=subscription }} disulfide bridges, and it appears related to insulin.{{cite journal | vauthors = Hossain MA, Rosengren KJ, Samuel CS, Shabanpoor F, Chan LJ, Bathgate RA, Wade JD | title = The minimal active structure of human relaxin-2 | journal = The Journal of Biological Chemistry | volume = 286 | issue = 43 | pages = 37555–65 | date = October 2011 | pmid = 21878627 | pmc = 3199501 | doi = 10.1074/jbc.M111.282194 | doi-access = free }}

Relaxin is produced from its prohormone, "prorelaxin", by post-translational proteolytic cleavage of its signal peptide and C domain peptide.{{cite book | vauthors = Roby KF | chapter = Relaxin |date=2019-01-01 | title = Reference Module in Biomedical Sciences |publisher=Elsevier |language=en |isbn=978-0-12-801238-3 }}

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.{{cite journal | vauthors = Hayes ES | title = Biology of primate relaxin: a paracrine signal in early pregnancy? | journal = Reproductive Biology and Endocrinology | volume = 2 | issue = 36 | pages = 36 | date = June 2004 | pmid = 15200675 | pmc = 449733 | doi = 10.1186/1477-7827-2-36 | doi-access = free }} Relaxin may be involved in the vital process of decidualisation, working alongside steroid hormones to allow the endometrium to prepare for implantation.{{cite journal | vauthors = Carp H, Torchinsky A, Fein A, Toder V | title = Hormones, cytokines and fetal anomalies in habitual abortion | journal = Gynecological Endocrinology | volume = 15 | issue = 6 | pages = 472–83 | date = December 2001 | pmid = 11826772 | doi = 10.1080/gye.15.6.472.483 | s2cid = 22623928 }} 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.{{Cite web |title=Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice - 8th Edition |url=https://www.elsevier.com/books/creasy-and-resniks-maternal-fetal-medicine-principles-and-practice/resnik/978-0-323-47910-3 |access-date=2022-09-29 |website=www.elsevier.com}} In pregnancy, relaxin mediates the hemodynamic changes that occur such as increased cardiac output and increased renal blood flow.{{Cite web |title=Pregnancy and Lactation - Endocrinology and Reproduction - Guyton and Hall Textbook of Medical Physiology, 12th Ed |url=https://doctorlib.info/physiology/textbook-medical-physiology/82.html |access-date=2022-09-29 |website=doctorlib.info |language=en}}{{cite journal | vauthors = Conrad KP | title = Maternal vasodilation in pregnancy: the emerging role of relaxin | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 301 | issue = 2 | pages = R267-75 | date = August 2011 | pmid = 21613576 | pmc = 3154715 | doi = 10.1152/ajpregu.00156.2011 }}

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.{{cite web |last1=Lambeth Hochwald |title=A Cheat Sheet to Pregnancy Hormones |url=https://www.parents.com/pregnancy/my-life/emotions/a-cheat-sheet-to-pregnancy-hormones/ |website=Parents}}

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.{{cite journal | vauthors = Weiss G | title = Relaxin in the male | journal = Biology of Reproduction | volume = 40 | issue = 2 | pages = 197–200 | date = February 1989 | pmid = 2497805 | doi = 10.1095/biolreprod40.2.197 | doi-access = free }}

In the cardiovascular system, relaxin is secreted by the heart{{cite journal | vauthors = Fisher C, MacLean M, Morecroft I, Seed A, Johnston F, Hillier C, McMurray J | title = Is the pregnancy hormone relaxin also a vasodilator peptide secreted by the heart? | journal = Circulation | volume = 106 | issue = 3 | pages = 292–295 | date = July 2002 | pmid = 12119241 | doi = 10.1161/01.CIR.0000025630.05387.45 | s2cid = 12420846 | doi-access = }} 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,{{cite journal | vauthors = Chen TY, Li X, Hung CH, Bahudhanapati H, Tan J, Kass DJ, Zhang Y | title = The relaxin family peptide receptor 1 (RXFP1): An emerging player in human health and disease | journal = Molecular Genetics & Genomic Medicine | volume = 8 | issue = 4 | pages = e1194 | date = April 2020 | pmid = 32100955 | pmc = 7196478 | doi = 10.1002/mgg3.1194 }} and matrix metalloproteinases transcription.{{cite journal | vauthors = Raleigh JM, Toldo S, Das A, Abbate A, Salloum FN | title = Relaxin' the Heart: A Novel Therapeutic Modality | journal = Journal of Cardiovascular Pharmacology and Therapeutics | volume = 21 | issue = 4 | pages = 353–362 | date = July 2016 | pmid = 26589290 | doi = 10.1177/1074248415617851 | s2cid = 4106451 }} In ex vivo experiments using subcutaneous resistance arteries, relaxin has shown to be a powerful endothelium-dependent vasodilator.

Via upregulation of VEGF, relaxin also plays a key role in blood vessel formation (angiogenesis) during pregnancy, tumour development or ischaemic wounds.{{cite journal |vauthors=Feijóo-Bandín S, Aragón-Herrera A, Rodríguez-Penas D, Portolés M, Roselló-Lletí E, Rivera M, González-Juanatey JR, Lago F |date=2017 |title=Relaxin-2 in Cardiometabolic Diseases: Mechanisms of Action and Future Perspectives |journal=Frontiers in Physiology |language=en |volume=8 |pages=599 |doi=10.3389/fphys.2017.00599 |pmc=5563388 |pmid=28868039 |doi-access=free}}

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. 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.{{cite journal | vauthors = Mookerjee I, Solly NR, Royce SG, Tregear GW, Samuel CS, Tang ML | title = Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease | journal = Endocrinology | volume = 147 | issue = 2 | pages = 754–61 | date = February 2006 | pmid = 16254028 | doi = 10.1210/en.2005-1006 | doi-access = free }} It also enhances angiogenesis and is a potent renal vasodilator.{{Citation needed|date=October 2018}}

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.{{cite journal |vauthors=Klein C |date=July 2016 |title=The role of relaxin in mare reproductive physiology: A comparative review with other species |journal=Theriogenology |volume=86 |issue=1 |pages=451–6 |doi=10.1016/j.theriogenology.2016.04.061 |pmid=27158127}} 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.{{cite journal |vauthors=Klein C |date=July 2016 |title=Early pregnancy in the mare: old concepts revisited |journal=Domestic Animal Endocrinology |volume=56 | issue = Suppl |pages=S212-7 |doi=10.1016/j.domaniend.2016.03.006 |pmid=27345319}} 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.{{cite journal |vauthors=Ousey JC |date=December 2006 |title=Hormone profiles and treatments in the late pregnant mare |journal=The Veterinary Clinics of North America. Equine Practice |volume=22 |issue=3 |pages=727–47 |doi=10.1016/j.cveq.2006.08.004 |pmid=17129800}} From 80 day of gestation onwards, relaxin levels will increase in the mare's serum with levels peaking in late gestation.{{cite journal |vauthors=Pashen RL |date=July 1984 |title=Maternal and foetal endocrinology during late pregnancy and parturition in the mare |journal=Equine Veterinary Journal |volume=16 |issue=4 |pages=233–8 |doi=10.1111/j.2042-3306.1984.tb01918.x |pmid=6383806}} 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.

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 and has been found to promote maturation of cardiomyocytes in mice.

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.{{Citation needed|date=October 2018}} 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 (Oryctolagus cuniculus), relaxin is associated with squamous differentiation and is expressed in tracheobronchial epithelial cells as opposed to being involved with reproduction.{{cite journal | vauthors = Arroyo JI, Hoffmann FG, Opazo JC | title = Gene duplication and positive selection explains unusual physiological roles of the relaxin gene in the European rabbit | journal = Journal of Molecular Evolution | volume = 74 | issue = 1–2 | pages = 52–60 | date = February 2012 | pmid = 22354201 | doi = 10.1007/s00239-012-9487-2 | bibcode = 2012JMolE..74...52A | s2cid = 15030230 }}

Relaxin interacts with the relaxin receptor LGR7 (RXFP1) and LGR8 (RXFP2), which belong to the G protein-coupled receptor superfamily.{{cite journal | vauthors = Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ | title = Activation of orphan receptors by the hormone relaxin | journal = Science | volume = 295 | issue = 5555 | pages = 671–4 | date = January 2002 | pmid = 11809971 | doi = 10.1126/science.1065654 | bibcode = 2002Sci...295..671H | s2cid = 32693420 }} 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.{{cn|date=September 2023}}

Relaxin receptors have been found in the heart, smooth muscle, the connective tissue, and central and autonomous nervous system.{{Citation needed|date=October 2018}}

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.{{cite journal | vauthors = Marshall SA, Senadheera SN, Parry LJ, Girling JE | title = The Role of Relaxin in Normal and Abnormal Uterine Function During the Menstrual Cycle and Early Pregnancy | journal = Reproductive Sciences | volume = 24 | issue = 3 | pages = 342–354 | date = March 2017 | pmid = 27365367 | doi = 10.1177/1933719116657189 | s2cid = 22443796 }} However, more research is needed to confirm relaxin as a direct cause.{{Citation needed|date=October 2018}}

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.{{cite journal | vauthors = Van Der Westhuizen ET, Summers RJ, Halls ML, Bathgate RA, Sexton PM | title = Relaxin receptors—new drug targets for multiple disease states | journal = Current Drug Targets | volume = 8 | issue = 1 | pages = 91–104 | date = January 2007 | pmid = 17266534 | doi = 10.2174/138945007779315650 }}

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.

Recombinant forms of human relaxin-2 such as volenrelaxin (LY3540378){{cite journal |last1=Almeida-Pinto |first1=Nísia |last2=Dschietzig |first2=Thomas Bernd |last3=Brás-Silva |first3=Carmen |last4=Adão |first4=Rui |title=Cardiovascular effects of relaxin-2: therapeutic potential and future perspectives |journal=Clinical Research in Cardiology |date=18 September 2023 |volume=113 |issue=8 |pages=1137–1150 |doi=10.1007/s00392-023-02305-1|pmid=37721595 |doi-access=free |pmc=11269324 |hdl=10216/150307 |hdl-access=free }}{{cite journal |last1=Verdino |first1=Petra |last2=Lee |first2=Stacey L. |last3=Cooper |first3=Fariba N. |last4=Cottle |first4=Steven R. |last5=Grealish |first5=Patrick F. |last6=Hu |first6=Charlie C. |last7=Meyer |first7=Catalina M. |last8=Lin |first8=Joanne |last9=Copeland |first9=Victoria |last10=Porter |first10=Gina |last11=Schroeder |first11=Richard L. |last12=Thompson |first12=Tyran D. |last13=Porras |first13=Leah L. |last14=Dey |first14=Asim |last15=Zhang |first15=Hong Y. |last16=Beebe |first16=Emily C. |last17=Matkovich |first17=Scot J. |last18=Coskun |first18=Tamer |last19=Balciunas |first19=Aldona M. |last20=Ferrante |first20=Andrea |last21=Siegel |first21=Robert |last22=Malherbe |first22=Laurent |last23=Bivi |first23=Nicoletta |last24=Paavola |first24=Chad D. |last25=Hansen |first25=Ryan J. |last26=Abernathy |first26=Matthew M. |last27=Nwosu |first27=Sylvia O. |last28=Carr |first28=Molly C. |last29=Heuer |first29=Josef G. |last30=Wang |first30=Xiaojun |title=Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure |journal=British Journal of Pharmacology |date=August 2023 |volume=180 |issue=15 |pages=1965–1980 |doi=10.1111/bph.16055|pmid=36780899 |doi-access=free }} and serelaxin (RLX030){{Citation needed|date=October 2018}} have been developed as investigational drugs.

It is suggested that relaxin could be used as a therapeutic target when it comes to gynaecological disorders.

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.{{cite journal | vauthors = Arroyo JI, Hoffmann FG, Opazo JC | title = Evolution of the relaxin/insulin-like gene family in anthropoid primates | journal = Genome Biology and Evolution | volume = 6 | issue = 3 | pages = 491–9 | date = March 2014 | pmid = 24493383 | pmc = 3971578 | doi = 10.1093/gbe/evu023 }} 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.

• Relaxin family peptide hormones
• Insulin/IGF/Relaxin family
• Relaxin/insulin-like family peptide receptor 1

{{Reflist|2}}

• {{MeshName|Relaxin'}}
• {{cite web | url = http://www.hprd.org/resultsQuery?multiplefound=&prot_name=Relaxin&external=Ref_seq&accession_id=&hprd=&gene_symbol=&chromo_locus=&function=&ptm_type=&localization=&domain=&motif=&expression=&prot_start=&prot_end=&limit=0&mole_start=&mole_end=&disease=&query_submit=Search | title = Relaxin | work = Human Protein Reference Database | publisher = Johns Hopkins University and the Institute of Bioinformatics | access-date = 2009-05-20 | archive-date = 2014-11-29 | archive-url = https://web.archive.org/web/20141129030456/http://www.hprd.org/resultsQuery?multiplefound=&prot_name=Relaxin&external=Ref_seq&accession_id=&hprd=&gene_symbol=&chromo_locus=&function=&ptm_type=&localization=&domain=&motif=&expression=&prot_start=&prot_end=&limit=0&mole_start=&mole_end=&disease=&query_submit=Search | url-status = dead }}

{{Hormones}}

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Category:Peptide hormones

Category:Hormones of the ovary

Category:Hormones of the placenta

Category:Hormones of the pregnant female

Category:Human female endocrine system