Relaxin

What is Relaxin?

Relaxin is a family of endogenous peptide hormones in the insulin superfamily. The dominant human circulating form is H2 relaxin (encoded by RLN2), a two-chain disulfide-bonded peptide cleaved from a pro-hormone by furin-like processing. It was first identified in 1926 as a pregnancy factor that relaxes the pelvic ligaments and cervix, and it is produced chiefly by the corpus luteum in women, with smaller contributions from decidua, placenta, and prostate. Relaxin acts at a set of related G-protein–coupled receptors — RXFP1 (the primary H2-relaxin receptor), RXFP2 (which binds INSL3), and RXFP3/RXFP4 (which bind the brain-expressed RLN3 and INSL5). The recombinant H2-relaxin drug serelaxin (RLX030) was developed by Corthera and then Novartis as a short-course intravenous therapy for acute heart failure but failed its pivotal Phase III RELAX-AHF-2 trial in 2019, and the program was halted. Relaxin has also been investigated for systemic sclerosis (scleroderma), organ fibrosis, and, more speculatively, anti-aging use.

What Relaxin Is Investigated For

Relaxin's strongest evidence base is physiological rather than therapeutic: decades of human and animal work establishing its role in pregnancy-associated pelvic-ligament softening, cervical ripening, and the systemic and renal vasodilation of early gestation. The therapeutic story is largely one of promising early signals that did not replicate in pivotal trials. The recombinant H2-relaxin drug serelaxin met a dyspnea endpoint and suggested a 180-day mortality benefit in the Phase III RELAX-AHF trial (2013), but the definitive RELAX-AHF-2 trial of 6,545 patients (2019) failed both co-primary endpoints — no reduction in 180-day cardiovascular death and no reduction in worsening heart failure through day 5 — and Novartis discontinued development. A parallel scleroderma program (initial Phase II signal from Seibold and colleagues in 2000; Phase III reported by Khanna in 2009) also failed its primary fibrosis endpoints and surfaced renal safety concerns. Organ-fibrosis and longevity framings are mostly preclinical and mechanistic. Outside clinical research settings, there is no approved therapeutic use; any 'research-use' relaxin marketed to consumers is trading on a mechanism story, not on validated outcome trials.

History & Discovery

Relaxin was discovered in 1926 by Frederick L. Hisaw, then at the University of Wisconsin, who showed that serum from pregnant guinea pigs and rabbits, when injected into virgin female guinea pigs, caused measurable relaxation of the pubic ligament within hours. That simple bioassay — later refined as the 'mouse interpubic ligament assay' — defined the unknown factor, which was named relaxin. For the next four decades, relaxin biology remained a niche area of reproductive endocrinology because the peptide was difficult to isolate and sequence compared to oxytocin and the vasopressins. The molecular era for relaxin began in the 1970s and 1980s with purification from porcine corpora lutea and subsequent cloning of the human RLN1 and RLN2 genes. H2 relaxin — the RLN2 product — emerged as the dominant circulating form in humans. In 2002 the receptors LGR7 and LGR8 (now RXFP1 and RXFP2) were deorphanized as relaxin and INSL3 receptors respectively, and shortly after, RXFP3 and RXFP4 were identified as receptors for relaxin-3 (RLN3) and INSL5. O. David Sherwood's 2004 Endocrine Reviews treatise consolidated the modern understanding of relaxin as a broad-acting peptide with roles extending well beyond pregnancy — vasodilation, anti-fibrotic action across multiple organs, and protection against ischemia-reperfusion injury. The therapeutic development arc was led in the 2000s by Connetics Corporation and then BAS Medical / Corthera, whose recombinant human relaxin product was licensed by Novartis and renamed serelaxin (RLX030). The acute heart failure program progressed through Pre-RELAX-AHF (Phase IIb, 234 patients, 2009), the Phase III RELAX-AHF trial (1,161 patients, 2013) that met one dyspnea co-primary endpoint and reported a 37% reduction in 180-day mortality, then to the definitive Phase III RELAX-AHF-2 trial (6,545 patients, 2019) — which failed both co-primary endpoints (180-day cardiovascular death and worsening heart failure through day 5) and ended the program. The FDA had granted serelaxin Breakthrough Therapy designation in 2013 on the strength of RELAX-AHF, but that designation did not translate into approval after the pivotal trial miss. A parallel scleroderma program (Connetics, Phase II positive in 2000, Phase III negative in 2009) followed a similar arc. Relaxin's therapeutic history is a textbook case of promising Phase II signal failing to replicate in a larger pivotal trial — and the field has largely moved toward next-generation RXFP1-selective agonists and longer-half-life analogs rather than further serelaxin development.

How It Works

Relaxin is a pregnancy-related hormone that softens connective tissue and widens blood vessels. It tells the body to remodel collagen, relax smooth muscle, and increase blood flow — changes that help prepare the pelvis and cervix for birth and that, researchers hoped, might help a failing heart. When tested as a drug (serelaxin) for acute heart failure, those effects weren't enough to improve outcomes in the definitive trial.

H2 relaxin binds to RXFP1 (relaxin family peptide receptor 1, formerly LGR7), a leucine-rich-repeat–containing G-protein–coupled receptor. RXFP1 activation triggers a characteristic biphasic cAMP response involving Gαs (rapid rise), PI3K- and PKCζ-dependent delayed amplification, and a modulating Gαi/o component with Gβγ release (Halls, Bathgate, and Summers, 2006). Downstream effects include nitric oxide / cGMP–mediated vasodilation, inhibition of TGF-β–driven myofibroblast activation, upregulation of matrix metalloproteinases (MMPs) with reciprocal downregulation of tissue inhibitors of metalloproteinases (TIMPs), and anti-inflammatory effects on vascular endothelium. During pregnancy, the corpus luteum secretes H2 relaxin into the circulation, driving pelvic ligament softening, cervical ripening, mammary development, and the systemic and renal vasodilation of early gestation (increased renal plasma flow, glomerular filtration rate, and vascular compliance). Conrad and colleagues' body of work established relaxin as a non-redundant mediator of several of these maternal hemodynamic adaptations. The relaxin family is broader than H2 alone. RXFP2 is the receptor for insulin-like peptide 3 (INSL3), involved in testicular descent and gubernaculum development. RXFP3, a Gi/o-coupled receptor expressed in the nucleus incertus and other brain regions, binds relaxin-3 (RLN3) and modulates arousal, stress responsiveness, hippocampal theta rhythm, and alcohol-seeking behavior in rodents. RXFP4 binds insulin-like peptide 5 (INSL5) and is expressed in the colon and elsewhere. The therapeutic rationale for serelaxin in acute heart failure combined RXFP1-mediated systemic and renal vasodilation, cardiac unloading, and potential anti-fibrotic / anti-ischemic end-organ protection over a 48-hour infusion window. The hypothesis failed in RELAX-AHF-2 despite a clean mechanistic story — a cautionary tale about extrapolating from Phase II dyspnea and mortality signals to hard outcomes in acute heart failure.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Relaxin:

• 01Why did the Phase III RELAX-AHF-2 trial fail despite the positive Phase II and RELAX-AHF signals? Candidates include the 30 mcg/kg/day dose being suboptimal, the 48-hour infusion window being too short, a patient-selection mismatch between the phases, or a genuine absence of the Phase II–suggested mortality effect. The field has not settled on a single explanation.
• 02Whether next-generation RXFP1-selective small-molecule agonists or engineered long-half-life relaxin analogs can deliver the mechanistic benefits suggested by preclinical anti-fibrotic data over chronic dosing windows, rather than the 48-hour acute infusion used in serelaxin trials.
• 03The precise contribution of relaxin vs. other mediators to pelvic-girdle pain and joint laxity in pregnancy — circulating relaxin levels correlate poorly with symptoms in most studies, despite persistent popular attribution.
• 04The role of RLN3/RXFP3 signaling in human neuropsychiatric conditions — rodent data implicates this system in arousal, stress responsiveness, hippocampal theta rhythm, and alcohol-seeking behavior, but human clinical translation is essentially absent.
• 05Long-term effects of chronic or repeated exogenous relaxin exposure on endogenous RXFP1 signaling, cardiovascular remodeling, and reproductive-axis hormones — no clinical data at the multi-year timescale exists.
• 06Whether relaxin's anti-fibrotic preclinical profile translates to a measurable healthspan or organ-function benefit in aging humans, which is the premise underlying the peripheral 'anti-aging' use case and is not supported by any controlled clinical trial.

Forms & Administration

The only clinical-grade formulation used in major trials was serelaxin (RLX030), recombinant human H2 relaxin, delivered as a 48-hour intravenous infusion at 30 mcg/kg/day in acute heart failure protocols. Recombinant relaxin in the scleroderma trials was delivered by continuous subcutaneous infusion over 24 weeks. No oral, nasal, or subcutaneous-bolus formulation has been approved or widely clinically tested. Research-grade or compounded relaxin sold outside approved channels has no verified purity, potency, or safety profile and does not reflect the formulation or delivery used in clinical trials. Any investigational peptide should only be used under appropriate medical supervision.

Common Questions

Who Relaxin Is NOT For

Drug & Supplement Interactions

Clinical interaction data for relaxin is largely limited to what was observed in the serelaxin heart failure trials. Hypotensive interactions are the most predictable concern — concurrent use with nitrates, other vasodilators, diuretics, or titrated beta-blocker therapy can produce additive reductions in blood pressure that in the RELAX-AHF trials required dose adjustment or infusion pause. Because relaxin is a peptide, it is not metabolized by CYP enzymes and classic pharmacokinetic drug-drug interactions through CYP pathways are not expected; rather, pharmacodynamic interactions at the hemodynamic level are the relevant category. Theoretical interactions with anti-fibrotic and immunomodulatory agents (pirfenidone, nintedanib, mycophenolate, tocilizumab) in scleroderma and organ-fibrosis contexts have not been characterized in controlled trials. Anticoagulants were used alongside serelaxin in heart failure trials without a major interaction signal, but the limited safety database means caution is appropriate. For off-label wellness or 'anti-aging' use, no formal interaction data exists at all — another reason that any investigational peptide use belongs under clinician supervision.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions