Hormones
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Relaxin

We’re about to dive into the wild world of Relaxin, the protein hormone that’s been turning heads since 1926 when Frederick Hisaw first stumbled upon it. This isn’t your average hormone – it’s a multitasking marvel that’s about to blow your mind! Researchers say this tiny protein, barely 6000 Da in size, is strutting around your body like it owns the place. And guess what? It kind of does! Relaxin is the Swiss Army knife of hormones, with more tricks up its sleeve than a magician at a kids’ party.

Let’s break it down:

Structure and Synthesis

Relaxin is like the cool cousin in the insulin family – structurally similar, but with its own unique flair. It’s a heterodimer, which is just a fancy way of saying it’s got two peptide chains (24 and 29 amino acids) linked by three disulfide bridges. It’s like a molecular tango, with two partners perfectly in sync.

But where does this wonder hormone come from? In females, it’s primarily produced by the corpus luteum, but during pregnancy, the placenta, chorion, and decidua join the party. Men aren’t left out – their prostates are churning out relaxin and adding it to their semen like a secret ingredient.

Functions (Hold onto your seats, folks!)

Reproduction: Relaxin is the ultimate multitasker in the baby-making business. It’s like the project manager of pregnancy, overseeing everything from implantation to delivery.

Cardiovascular System: Relaxin moonlights as a vasodilator, opening up those blood vessels like it’s Black Friday at the mall. It’s all about that nitric oxide pathway, baby!

Connective Tissue Remodeling: This hormone is the body’s own renovation crew, softening ligaments and preparing the birth canal for the big day.

Angiogenesis: Relaxin’s got a green thumb when it comes to blood vessels, promoting their growth during pregnancy, tumor development, and even in healing wounds.

Endocrine Regulation: It’s not just about babies – relaxin’s got its fingers in the pituitary pie too, influencing hormone secretion like a puppet master.

The Plot Thickens

But wait, there’s more! Recent studies have shown that relaxin might be the unsung hero of endometrial preparation. It’s like the interior decorator of the uterus, stimulating angiogenesis, maintaining connective tissue integrity, and even regulating those pesky estrogen and progesterone receptors.

And let’s not forget its potential as a cervical ripening agent. That’s right, relaxin might be the key to inducing labor without all the fuss5. It’s like the locksmith of the reproductive system, getting everything ready for the big exit!

So there you have it, folks. Relaxin: the hormone that’s been quietly running the show since before we even knew it existed. It’s in your ovaries, your prostate, your heart, and maybe even in your future as a therapeutic agent. Who knew such a tiny protein could pack such a punch?

Remember, the next time someone tells you to “relax,” you can tell them your body’s already on it – one molecule of relaxin at a time!

Other Notes (Wikipedia)

Structure

See also: Insulin/IGF/Relaxin family

Structurally, relaxin is a heterodimer of two peptide chains of 24 and 29 amino acids linked by three[7] disulfide bridges, and it appears related to insulin.[8]

Relaxin is produced from its prohormone, “prorelaxin”, by post-translational proteolytic cleavage of its signal peptide and C domain peptide.[9]

Function in humans

Reproduction

In females, relaxin is produced mainly by the corpus luteum, in both pregnant and nonpregnant females.[1] Relaxin levels rise to a peak within approximately 14 days of ovulation, and then decline in the absence of pregnancy, resulting in menstruation.[10] Relaxin may be involved in the vital process of decidualisation, working alongside steroid hormones to allow the endometrium to prepare for implantation.[11] 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.[12] In pregnancy, relaxin mediates the hemodynamic changes that occur such as increased cardiac output and increased renal blood flow.[13][14]

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.[15]

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.[16]

Cardiovascular function

In the cardiovascular system, relaxin is secreted by the heart[17] 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,[18] and matrix metalloproteinases transcription.[19] In ex vivo experiments using subcutaneous resistance arteries, relaxin has shown to be a powerful endothelium-dependent vasodilator.[17]

Via upregulation of VEGF, relaxin also plays a key role in blood vessel formation (angiogenesis) during pregnancy, tumour development or ischaemic wounds.[20]

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.[13] 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.[21] It also enhances angiogenesis and is a potent renal vasodilator.[citation needed]

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.[22] 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.[22] Furthermore, granular and theca cells in the follicles will express relaxin in increasing levels depending on their size.[22] During early pregnancy, the preimplantation conceptus will express relaxin, which will promote angiogenesis in the endometrium by up-regulating VEGF.[22][23] 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.[22]

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.[22] 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.[24] From 80 day of gestation onwards, relaxin levels will increase in the mare’s serum with levels peaking in late gestation.[24][25] Moreover, the pattern of relaxin expression will follow the expression of oestrogen, however, there is not yet a known link between these two hormones.[25] 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.[22][24] 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.[24] In addition, if the mare undergoes an abortion then the relaxin levels will decline as the placenta ceases to function.[24]

Cardiovascular 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.[19] Relaxin increases the rate and force of cardiac contraction in rat models and has been found to promote maturation of cardiomyocytes in mice.[20]

Several animal studies have found relaxin to have a cardioprotective function against ischemia and reperfusion injury, by reducing cellular damage, via anti-apoptotic and anti-inflammatory effects.[citation needed] Relaxin has been shown to reduce cardiac fibrosis in animal models by inhibiting cardiac fibroblasts secreting collagen and stimulating matrix metalloproteinase.[20][19]

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.[26]

Receptors

Relaxin interacts with the relaxin receptor LGR7 (RXFP1) and LGR8 (RXFP2), which belong to the G protein-coupled receptor superfamily.[27] 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.[citation needed]

Relaxin receptors have been found in the heart, smooth muscle, the connective tissue, and central and autonomous nervous system.[citation needed]

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.[28] However, more research is needed to confirm relaxin as a direct cause.[citation needed]

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.[28]

Specific disorders related to relaxin have not been heavily described, yet a link to scleroderma and fibromyalgia has also been suggested.[29]

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.[28]

Pharmacological targets

A recombinant form of human relaxin-2 has been developed as investigational drug RLX030 (serelaxin).[citation needed]

It is suggested that relaxin could be used as a therapeutic target when it comes to gynaecological disorders.[28]

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.[30] 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.[30] 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.[30]

See also

References

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  27. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ (January 2002). “Activation of orphan receptors by the hormone relaxin”. Science. 295 (5555): 671–4. Bibcode:2002Sci…295..671H. doi:10.1126/science.1065654. PMID 11809971. S2CID 32693420.
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