Human Relaxin-2

Relaxin-2, encoded by the RLN2 gene, is the major circulating relaxin in humans and a member of the insulin and relaxin peptide superfamily ^[3]. Like insulin, it is a small protein of roughly 6 kilodaltons built from two peptide chains, designated the A and B chains, that are joined by disulfide bonds ^[3]. The name relaxin was coined for the hormone's early-recognized ability to relax the pelvic ligaments, yet its actions are now known to be far broader.

In women, relaxin-2 is produced chiefly by the corpus luteum of the ovary, with additional synthesis in the breast, the uterine lining, and the placenta; in men it is made in the prostate and is present in semen ^[3]. Circulating levels rise notably during pregnancy, when the corpus luteum secretes the hormone into the bloodstream ^[2]. Its widespread receptor distribution across reproductive and non-reproductive tissues reflects the diversity of its roles ^[1].

The hormone is best understood in the setting of pregnancy, where it helps drive the profound cardiovascular and renal adaptations of the pregnant state, including increased cardiac output, greater renal blood flow, and a rise in glomerular filtration ^[2]. It also remodels reproductive tissues, softening the cervix, loosening the pubic symphysis and pelvic ligaments, and preparing the uterus, and it contributes to the growth of new blood vessels ^[3]. Reduced relaxin in early pregnancy has been linked with an increased risk of complications such as miscarriage and preeclampsia ^[3].

Relaxin-2 acts through a G-protein-coupled receptor known as RXFP1, originally identified as the orphan receptor LGR7, while a related receptor, RXFP2, mediates the actions of a distinct family member ^[1]. The discovery that these orphan receptors respond to relaxin clarified how a hormone with such wide-ranging effects transmits its signal ^[1].

Because of its vasodilatory and tissue-protective properties, relaxin-2 drew interest as a potential therapeutic. A recombinant form, serelaxin, was developed and tested for acute heart failure, where an early trial suggested improvements in symptoms and hinted at a survival benefit ^[5]. A subsequent large, definitive trial, however, found that serelaxin did not reduce cardiovascular death or improve the outcomes it was designed to address, which tempered enthusiasm for the approach ^[4]. Research into relaxin-based therapies and newer analogs has continued.

Relaxin-2 itself is an endogenous human hormone rather than a marketed product, and its recombinant therapeutic form, serelaxin, remained investigational and was not approved for general clinical use after the pivotal heart failure trials ^[4][5]. The hormone continues to be a subject of research in cardiovascular, renal, and reproductive medicine, and as a target for engineered relaxin-like molecules.

In trials as serelaxin it was generally well tolerated, with low blood pressure being the main concern given its vasodilatory action. Long-term and non-pregnancy human data outside of heart failure are limited. Unregulated research-peptide versions carry the usual purity and dosing uncertainties.