Relaxin: The Pregnancy Peptide That Loosens Joints
Pregnancy Peptides
10x increase during first trimester
Relaxin levels rise tenfold in the first trimester, remodeling the pelvis for childbirth while affecting joints throughout the body and protecting the cardiovascular system.
Ferlin et al., British Medical Bulletin, 2017
Ferlin et al., British Medical Bulletin, 2017
View as imageRelaxin is best known for the thing that makes pregnant women's joints feel unstable. It is a peptide hormone that remodels connective tissue by activating matrix metalloproteinases (MMPs), the enzymes that break down collagen and other structural proteins. During pregnancy, this remodeling loosens the pelvic ligaments to allow the birth canal to expand. But relaxin is far more than a pregnancy hormone. It is a vasodilator, an anti-fibrotic agent, and a modulator of the cardiovascular system that has been tested in clinical trials for heart failure.[1] The oxytocin and breastfeeding article covers another key reproductive peptide. This article covers relaxin's biology, its effects beyond reproduction, and its therapeutic potential.
Key Takeaways
- Relaxin is a two-chain peptide structurally related to insulin, produced primarily by the corpus luteum during pregnancy, with levels peaking in the first trimester at concentrations roughly 10 times non-pregnant levels
- Relaxin activates matrix metalloproteinases (MMP-1, MMP-2, MMP-9, MMP-13) that degrade collagen in ligaments, tendons, and the cervix, preparing the pelvis for childbirth (Ferlin et al., British Medical Bulletin, 2017)
- Four relaxin family peptide receptors (RXFP1-4) have been identified, each mediating different biological effects in different tissues
- Serelaxin (recombinant relaxin-2) showed early promise for acute heart failure in the RELAX-AHF trial but failed to meet primary endpoints in the larger RELAX-AHF-2 trial (Voors et al., 2025)
- Sustained-release relaxin-2 microparticles reversed arthrofibrosis (joint scarring) in animal models, suggesting therapeutic applications for fibrotic conditions (Kirsch et al., 2022)
- Relaxin-3, expressed primarily in the brain, acts on RXFP3 receptors to regulate stress, anxiety, feeding behavior, and arousal, distinct from relaxin-2's peripheral effects (Riches et al., 2026)
Structure and the Insulin Connection
Relaxin belongs to the insulin superfamily, a group of structurally related peptides that includes insulin, insulin-like growth factors (IGF-1 and IGF-2), and the insulin-like peptides (INSL3-6). Like insulin, relaxin is a two-chain peptide: an A-chain and a B-chain linked by two interchain disulfide bonds, with an additional intrachain disulfide bond in the A-chain.
Hossain, Wade, and Bathgate demonstrated the functional importance of this architecture in 2012 by creating chimeric relaxin peptides that swapped the A-chains between different relaxin family members. They found that the A-chain is not merely a structural scaffold; it directly influences receptor binding and biological activity. Chimeras with mismatched A-chains showed reduced potency at RXFP1, establishing that both chains contribute to receptor recognition.[2]
Three forms of relaxin exist in humans: relaxin-1 (H1), relaxin-2 (H2), and relaxin-3 (H3). Relaxin-2 is the circulating form responsible for reproductive and cardiovascular effects. Relaxin-3 is expressed primarily in the nucleus incertus of the brainstem and functions as a neuropeptide. Relaxin-1 has no clearly defined physiological role and may be a pseudogene product.
How Relaxin Remodels Connective Tissue
Relaxin's effects on joints and ligaments operate through a well-characterized enzymatic cascade. When relaxin binds RXFP1 receptors on fibroblasts and other connective tissue cells, it triggers increased expression and activation of matrix metalloproteinases, specifically collagenases (MMP-1 and MMP-13) and gelatinases (MMP-2 and MMP-9). These enzymes cleave collagen fibers, reducing the tensile strength and stiffness of ligaments, tendons, and the cervix.
Ferlin and colleagues reviewed the musculoskeletal effects comprehensively in 2017, documenting relaxin's involvement in bone remodeling, ligament healing, and skeletal muscle regeneration beyond its pregnancy role.[1]
During pregnancy, the primary target is the pubic symphysis and sacroiliac joints, which must become more flexible to allow passage of the fetal head during delivery. But relaxin circulates systemically, and its effects are not limited to the pelvis. Pregnant women commonly report increased laxity in the knees, ankles, wrists, and spine. This systemic effect explains the increased incidence of ankle sprains, ACL injuries, and carpal tunnel syndrome during pregnancy. The joint instability typically resolves within months after delivery as relaxin levels return to baseline.
The relationship between relaxin and BPC-157's effects on fibroblasts and collagen provides an interesting contrast: BPC-157 promotes collagen synthesis, while relaxin promotes its degradation. Both peptides act on fibroblasts but push connective tissue remodeling in opposite directions.
The Four Relaxin Receptors
The relaxin system operates through four G-protein coupled receptors with distinct tissue distributions and functions:
RXFP1 is the primary receptor for relaxin-2. It is expressed in reproductive tissues (uterus, cervix, ovary, prostate), the cardiovascular system (heart, blood vessels, kidneys), and connective tissue. RXFP1 activation increases cAMP, activates nitric oxide synthase, and upregulates MMP expression. This is the receptor responsible for both the connective tissue remodeling and vasodilatory effects of relaxin.
RXFP2 is the receptor for INSL3 (insulin-like peptide 3) and is primarily involved in testicular descent during fetal development and male fertility. Relaxin-2 has low affinity for RXFP2.
RXFP3 is the receptor for relaxin-3 in the brain. It modulates arousal, stress responses, feeding behavior, and anxiety. Riches and colleagues published a comprehensive review of relaxin-3 analog development and RXFP3 signaling in 2026, documenting how synthetic relaxin-3 peptides are being developed as potential treatments for anxiety, depression, and eating disorders.[3]
RXFP4 is activated by INSL5, a gut-expressed peptide involved in appetite regulation and colonic motility. RXFP4 agonists are being investigated for constipation.
The existence of four receptors with different ligands and tissue distributions means that relaxin-based therapeutics can potentially be designed for highly specific applications by targeting individual receptor subtypes. A drug that selectively activates RXFP1 could produce vasodilation and anti-fibrotic effects without triggering RXFP3-mediated changes in appetite or anxiety. Conversely, a selective RXFP3 agonist could modulate stress and feeding behavior without affecting blood pressure or connective tissue integrity. This receptor selectivity is a major advantage of the relaxin system compared to less specific peptide targets.
Relaxin and the Heart
Outside pregnancy, relaxin's most studied therapeutic application is cardiovascular disease. Relaxin-2 is a potent vasodilator that increases arterial compliance, reduces vascular resistance, and promotes renal blood flow. During pregnancy, these effects contribute to the 40-50% increase in cardiac output that supports fetal growth.
Serelaxin (recombinant human relaxin-2) was developed by Novartis for acute heart failure. The RELAX-AHF trial showed promising results: serelaxin improved dyspnea (shortness of breath) through day 5, reduced worsening heart failure by 47%, and decreased cardiovascular mortality by 37% at 180 days compared to placebo. These results led to the larger RELAX-AHF-2 trial.
Voors and colleagues published the biomarker substudy of RELAX-AHF-2 in 2025. While the main trial failed to meet its primary endpoints of reduced cardiovascular death at day 180 and reduced worsening heart failure at day 5, the biomarker analysis showed that serelaxin had beneficial effects on markers of end-organ damage. Kidney injury markers, liver function tests, and cardiac biomarkers all showed improvements in the serelaxin group, suggesting the drug was protecting organs even if the clinical endpoints were not met.[4]
The disconnect between organ protection and clinical outcomes remains unexplained. Possible explanations include insufficient dosing, wrong timing of administration (serelaxin was given as a 48-hour infusion starting at hospital admission), the heterogeneity of the acute heart failure population, or the possibility that organ protection takes longer than 180 days to translate into survival benefit. The RELAX-AHF-2 trial enrolled over 6,500 patients across 300 sites, making it one of the largest acute heart failure trials ever conducted. Its failure was a significant setback for the relaxin cardiovascular program. Serelaxin development has largely stalled, though the biomarker data keep the biological rationale alive, and some researchers argue the drug was tested in the wrong population or at the wrong dose. The vasodilatory and anti-fibrotic properties of relaxin remain biologically compelling for cardiovascular disease even if the clinical development path proved difficult. The article on BNP and NT-proBNP in heart failure diagnosis provides context on how peptide biomarkers are used to monitor heart failure.
Relaxin as an Anti-Fibrotic Agent
Fibrosis, the excessive accumulation of scar tissue, drives disease progression in the liver, lungs, kidneys, and joints. Relaxin opposes fibrosis by inhibiting TGF-beta/Smad signaling, the central pathway that activates fibroblasts and drives collagen overproduction. It also directly upregulates MMPs that degrade existing scar tissue.
Kirsch and colleagues demonstrated a therapeutic application of this anti-fibrotic activity in 2022. They created sustained-release microparticles loaded with relaxin-2 and injected them into joints with arthrofibrosis (excessive scar tissue that restricts range of motion after surgery or injury). The relaxin microparticles reversed the fibrosis, restoring joint mobility in animal models. The sustained-release formulation addressed a key limitation of relaxin therapy: the peptide's short half-life of approximately 10 minutes in circulation.[5]
This approach has implications for conditions ranging from frozen shoulder to hepatic fibrosis to pulmonary fibrosis, all of which involve excessive TGF-beta-driven collagen deposition that relaxin could theoretically reverse.
Relaxin-3: A Brain Peptide, Not a Pregnancy Hormone
Relaxin-3 is evolutionarily the oldest member of the relaxin family and is functionally distinct from relaxin-2. It is produced almost exclusively in the nucleus incertus of the brainstem and acts through RXFP3 receptors in the hypothalamus, amygdala, and hippocampus.
Wu and colleagues at the Florey Institute in Melbourne have been systematically developing tools to study the relaxin-3/RXFP3 system. In 2025, they published the design of structurally stabilized B-chain antagonists targeting RXFP3, compounds that block the receptor without activating it. These tools are critical for understanding what RXFP3 does in the brain and for developing potential therapeutics.[6]
The same group created chimeric relaxin-3/INSL5 peptides in 2024 to probe the overlap between RXFP3 and RXFP4 signaling, revealing how subtle changes in peptide structure determine receptor selectivity.[7]
Haugaard-Kedstrom and colleagues characterized the binding determinants of a single-chain RXFP3 antagonist in 2018, establishing which residues in the relaxin-3 B-chain are essential for receptor recognition.[8]
Animal studies suggest that RXFP3 modulates stress-induced anxiety, food-seeking behavior, arousal, and memory formation. Blocking RXFP3 reduces stress-induced feeding and anxiety-like behavior in rodents. Activating it promotes wakefulness and exploration. Whether these effects translate to human therapeutics remains to be determined, but the development of stable, selective RXFP3 ligands is a prerequisite for clinical testing.
The brain-specific distribution of relaxin-3 makes it an unusual member of the relaxin family. While relaxin-2 operates as a classic endocrine hormone (secreted into the bloodstream to act on distant tissues), relaxin-3 functions as a neurotransmitter-like peptide released at specific synapses. This distinction is important because it means relaxin-3-based drugs would need to cross the blood-brain barrier, a challenge that peripheral relaxin-2 drugs do not face. The structural similarity between relaxin-2 and relaxin-3 means that developing receptor-selective compounds requires careful engineering of the B-chain residues that determine receptor preference.
Relaxin During Pregnancy: What the Timeline Looks Like
Relaxin levels follow a characteristic pattern during pregnancy. The corpus luteum begins producing relaxin shortly after implantation. Levels rise rapidly during the first trimester, peaking at approximately 10 times non-pregnant concentrations around week 12. After the first trimester, levels decline somewhat but remain elevated throughout pregnancy.
The early peak corresponds to the period when the uterus must expand rapidly and the cervical tissue begins its months-long softening process. The oxytocin in labor article covers what happens at the other end of pregnancy, when oxytocin drives the contractions that relaxin's tissue remodeling has made possible. The placental peptide hormones article covers other peptides produced during pregnancy.
In men, relaxin is produced by the prostate gland and is present in seminal fluid at concentrations comparable to peak pregnancy levels in women. The peptide may promote sperm motility and facilitate implantation by modifying the cervical and uterine environment after intercourse. The prostate is one of the richest sources of RXFP1 expression outside the female reproductive tract, and elevated relaxin levels have been associated with prostate cancer progression, though the causal relationship is debated. The article on GLP-1 drugs and pregnancy covers a different but related topic: how peptide drugs interact with the reproductive system.
The Bottom Line
Relaxin is a two-chain peptide from the insulin superfamily that remodels connective tissue during pregnancy by activating collagen-degrading enzymes. Beyond reproduction, it is a vasodilator, an anti-fibrotic agent, and a brain neuropeptide (relaxin-3/RXFP3). Serelaxin showed organ-protective effects in heart failure but failed to improve clinical outcomes in Phase 3. Sustained-release formulations for joint fibrosis and RXFP3-targeted brain therapeutics represent the most active current research directions.