The PubMed and Web of Science databases were used to find relevant literature published between 1 October 2015 and 1 October 2025. The search terms included “pelvis, pelvic, tendinopathy, pelvic tendinopathy, tendon, arcus tendineus levator ani, arcus tendineus fascia pelvis”, and related keywords. Comprehensive searches were performed using scientifically rigorous search strategies.

The ATFP and ATLA represent tendon-like connective-tissue specializations within the pelvic floor that distribute mechanical loads across the endopelvic fascia-levator ani continuum. Their ability to support the pelvic organs and maintain continence relies on a hierarchically organized ECM. This is integrated with a resident fibroblastic cell population that senses, transmits, and adapts to repetitive mechanical strain. Therefore, it is essential to define the anatomical configuration and molecular composition of ATFP and ATLA to understand why they are susceptible to degeneration during childbirth and during age-related changes in matrix turnover.

The ATFP is a band of tissue that runs from the ischial spine (part of the pelvis) to the pubic bone in the center and front of the pelvis. It is attached to the inner pelvic muscle (the obturator internus muscle) and holds up the pelvic organs, such as the bladder and rectum [21]. The ATLA, often referred to as the second white line, originates in association with the iliococcygeus muscle [22]. Although these two tendinous arches are mechanically coupled, they fulfil distinct roles. The ATFP primarily resists the sustained tensile loads associated with organ suspension. In contrast, the ATLA accommodates the cyclic deformation and force transmission generated by active muscle contraction.

At the molecular level, the ECM of both ATFP and ATLA is dominated by structural proteins that jointly determine stiffness, extensibility, and resistance to fatigue damage. Collagen is the main load-bearing component, with type I collagen (COLI) accounting for 85–90% of the total collagen content and providing high tensile strength under mechanical loading [1]. Type III collagen (COLIII) contributes to compliant behavior and is commonly associated with matrix remodeling following microtrauma [23]. Minor collagens, including types IV, V, and VI, are involved in the organization of basement membranes and the assembly of fibrils, thereby supporting cell–matrix interactions and matrix architecture [24]. Elastin, which typically comprises 1–2% of the ECM, provides recoil and elastic recovery, enabling adaptation to cyclic deformation during fluctuations in intra-abdominal pressure [25]. Meanwhile, glycoproteins such as fibronectin help to form fibrils and attach cells to each other. Proteoglycans, including decorin and versican, control the spacing of fibrils, the amount of water they contain, and their stretchiness [26]. These different components work together to provide a balance between stability and flexibility, which is important for supporting the body’s weight.

Maintenance and remodeling of the ECM is predominantly mediated by tenocytes (specialized fibroblasts aligned along collagen fibrils) that coordinate matrix synthesis, organization, and turnover in response to mechanical cues [3, 27]. Interfascicular tenocytes help to connect tissues at the points where they meet, while intrafascicular tenocytes control fiber alignment and strength of the tissues. Tendon stem/progenitor cells (TSPCs) are found in special areas around blood vessels. They can create new cells and also become different types of cells. They are distinguished from mature tenocytes (a type of connective tissue cell) by their expression of markers such as scleraxis (Scx) and tenomodulin (Tnmd). When TSPCs are under pressure or have been injured, they can move towards the damaged area and transform into cells that help to repair the tissue [28]. However, when conditions worsen, the cell function changes, the matrix composition is altered, or stressors in the body induce incorrect repair of the cell populations, this can lead to problems with the ECM.

Although ATFP and ATLA share core ECM constituents, the available evidence suggests their molecular composition is adapted to their distinct mechanical demands. The ATFP anchors the endopelvic fascia to the pelvic sidewall and is enriched in COLI and fibronectin, consistent with it being a suspensory structure optimized for resisting sustained tensile loads [29]. The ATLA has more elastin and proteoglycan than other similar tissues, helping it to support the pelvic floor during contraction [5]. At the levator ani attachment zone, fibrochondrocytes embedded within a collagen-rich matrix may facilitate graded load transfer between muscle contraction and the tendon-like arch. In contrast, the ATFP-endopelvic fascia interface is dominated by fibroblasts that maintain fascial integrity and flexibility by continuously producing ECM [30]. A comparative summary of the anatomical, molecular, and biomechanical features of ATFP and ATLA is provided in Table 1 (Ref, [4, 5, 6, 14, 15, 16, 19, 21, 22, 23, 27, 31, 32, 33, 34]).

ATFP and ATLA are both tendon-like pelvic structures with collagen I–dominant ECMs whose organization and cellular composition support load transmission and adaptive remodeling under physiological strain [1, 22, 26]. The extent to which the reported compositional differences between ATFP and ATLA reflect intrinsic specialization rather than inter-individual, methodological, or age-related variability remains unclear [5]. Research that examines the structure of these tissues, their component cells, and how they behave, and the forces acting on them, may reveal a direct link between the tissue architecture and how easily ATFP may be damaged compared to ATLA.

Progressive ECM remodeling is the central pathological process in pelvic tendinopathy, affecting the ATFP and ATLA. There is now substantial evidence that ATFP degeneration is not caused by a single factor, but instead by a combination of mechanical overload and biological modifiers that influence how tissues respond, and how quickly they repair themselves. These modifiers (hormonal remodeling, inflammatory signaling, oxidative stress, and systemic metabolic disturbance) affect matrix homeostasis and cell fate, explaining why similar mechanical exposures can lead to very different structural and clinical outcomes.

Genetic and transcriptomic observations support ECM dysregulation and fibroblast survival as core elements of pelvic floor connective-tissue failure. In the first exome chip study of POP, Kluivers et al. [35] identified four interrelated biological processes operating across epithelial cells, fibroblasts, and the surrounding ECM of the female urogenital tract: epithelial–mesenchymal transition, immune response activation, ECM modulation, and fibroblast survival/apoptosis. Since these processes are very similar to the degenerative cascades described in other load-bearing connective tissues, ATFP degeneration can be viewed as a failure of adaptive remodeling rather than as an isolated structural rupture.

Pregnancy and childbirth can lead to hormonal and molecular changes that overlap with features seen in pelvic floor problems, such as immune system activation and changes in how the body regulates connective tissue [36, 37]. During the peripartum susceptibility window—defined here as the interval from late pregnancy through early postpartum, and characterized by accelerated connective-tissue remodeling under high mechanical demand—elevated relaxin and estrogen levels promote matrix softening and extensibility to accommodate parturition [38]. The matrix metalloproteinases (MMPs) showing the strongest association with POP are MMP-1, MMP-2, and MMP-9. MMP-1 is an interstitial collagenase that can cleave COLI, while MMP-2 and MMP-9 are gelatin-degrading enzymes that can also break down the cleavage products of MMP-1 [39]. Relaxin has been shown to activate MMPs, particularly MMP-1 and MMP-13, causing collagen to break down and reduce skin strength [40].

It is very important to consider the context in studies of pelvic tendinopathy. Ferlin et al. [40] showed that relaxin activates a specific protein in tendon fibroblasts. Estrogen also makes tissue more elastic and increases the flexibility of connective tissue. These changes help the body cope with childbirth, but can also make it more difficult to resist excessive strain under high mechanical loads [41]. Substantial inter-individual variability exists, and not all women with elevated levels of peripartum relaxin develop pelvic tendinopathy. This suggests the presence of modifying factors, such as genetic variation (e.g., COL1A1 polymorphisms [42]) and the quality of the baseline matrix. Notably, much of the mechanistic evidence is derived from animal or non-pelvic tendon models [40], indicating a need for longitudinal human studies that directly examine ATFP responsiveness across the pregnancy and postpartum recovery periods.

Of all the contributing factors, mechanical overload is the most direct and consistently implicated trigger of ATFP and ATLA injury. Vaginal delivery can expose these tendinous arches to forces that exceed physiological tolerance, resulting in microtears, partial- or full-thickness disruption, or avulsion injuries, particularly at the levator ani attachment to the ATLA [15, 16]. Prolonged labor, fetal macrosomia, and operative deliveries using forceps or vacuum extraction further increase the strain magnitude and duration, and hence the risk of structural compromise.

Experimental studies in animals demonstrate that excessive mechanical loading suppresses gene programs associated with orderly wound healing, while activating stress-responsive and inflammatory mediators such as prostaglandin endoperoxide synthase 2 (Ptgs2), leading to impaired repair [43]. Complementary in vitro and in vivo data show that mechanically stressed tendon cells release extracellular vesicles that promote macrophage recruitment and amplify local immune signaling [44]. While these observations derive primarily from non-pelvic tendon systems, they offer insights into how acute overload can trigger a cascade of maladaptive responses in the ATFP, particularly when it coincides with the hormone-sensitive peripartum state.

The absence of a classic acute inflammatory infiltrate does not exclude a role for inflammation in pelvic tendinopathy [45]. Instead, inflammation is increasingly being conceptualized as a phase-dependent modulator whose influence varies throughout the processes of injury initiation, propagation, and chronic degeneration. This concept reconciles conflicting views in the literature. While some researchers emphasize inflammation as a key driver of tendinopathy, others characterize chronic disease as primarily degenerative [46].

Molecular evidence suggests that inflammatory signaling is most prominent during the early, often asymptomatic stages of repetitive microtrauma [21]. Pro-inflammatory cytokines (e.g., interleukin-1 beta [IL-1$\beta$] and tumor necrosis factor-alpha [TNF-$\alpha$]) activate certain MMPs, which in turn accelerate collagen breakdown. Alarmins like high mobility group box 1 [HMGB1] also worsen inflammation by activating toll-like receptor 4 [TLR4]/nuclear factor kappa-light-chain-enhancer of activated b cells [NF-$\kappa$B] pathways [47], while dysregulated lipid mediators (e.g., prostaglandins) sustain inflammatory tone [46]. As degeneration worsens, ongoing low-grade swelling can lead to excessive deposition of collagen III and the formation of scars, which may reduce tissue elasticity and strength [11]. Much of our understanding about how inflammation is regulated comes from studies of non-pelvic tendons, such as the Achilles tendon [46], with little known about the regulation of inflammation in the pelvis [11].

Macrophages play a key regulatory role in this phase-dependent framework. Classically activated M1 macrophages are important for early inflammatory responses, whereas alternatively activated M2 macrophages are important for resolving inflammation and repairing tissue damage. Research into the damage and repair of animal tendons has revealed that the ‘macrophage’ cell type affects the speed with which the tendon can be restored and how well it regenerates after damage [48, 49]. M1 macrophages release cytokines (e.g., IL-1$\beta$ and TNF-$\alpha$) and enzymes (e.g., MMP-9) that break down tissue during the initial phase of injury, helping to clear away dead tissue. However, if these macrophages are constantly activated, they can worsen tissue breakdown. On the other hand, M2 macrophages help repair tissue by producing cytokines such as IL-10 and TGF-$\beta$1, which promote collagen production and tenocyte growth [50, 51]. Although extrapolation to ATFP must be made cautiously, these data suggest that dysregulated macrophage polarization may bias pelvic tendineus arche healing toward degeneration rather than restoration [52, 53]. Targeting macrophage polarization via M2-promoting biomaterials or cytokines has emerged as a potential treatment strategy to restore ECM homeostasis in tendinopathy [54].

Oxidative stress, characterized by excessive production of reactive oxygen species (ROS), acts as a secondary amplifier of tendon degeneration by impairing cellular viability and matrix integrity [55]. ROS activate pathways that respond to stress, including c-Jun N-terminal kinase (JNK) phosphorylation, leading to increased MMP activity and accelerated collagen breakdown [56]. At the same time, ROS-induced cell death (apoptosis) reduces the viability of tenocytes and progenitor cells, while senescent cells begin to produce cytokines that perpetuate inflammatory and matrix-degrading signals [32]. The molecular pathogenesis described above is depicted in Fig. 1.

Fig. 1.

Hormonal, biomechanical, inflammatory, and oxidative stress pathways impair ATFP/ATLA regeneration. Tenocyte niche: the microenvironment supporting tenocyte survival and function. Relaxin activates matrix metalloproteinases (MMPs), degrading collagen and reducing tendon strength, while estrogen increases ATFP/ATLA elasticity, predisposing to overextension. Mechanical overload induces prostaglandin endoperoxide synthase 2 (Ptgs2) and tendon cell-derived extracellular vesicles, promoting macrophage recruitment and injury. interleukin-1 beta (IL-1$\beta$) and tumor necrosis factor-alpha (TNF-$\alpha$) upregulate MMPs, degrading extracellular matrix (ECM), while high mobility group box 1 (HMGB1) activates toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated b cells (NF-$\kappa$B), further hindering regeneration. Reactive oxygen species (ROS) drive c-Jun N-terminal kinase (JNK) phosphorylation and caspase-3-mediated apoptosis, increasing MMP activity and collagen breakdown (Created in BioRender. (2025) https://BioRender.com/lg61sfz).

Systemic metabolic disorders, including diabetes mellitus and hypercholesterolemia, can also influence tendon homeostasis and repair capacity [56]. An in vitro study found that high glucose levels induce mitochondrial dysfunction and ferroptosis—an iron-dependent form of regulated cell death—in TSPCs, impairing their capacity to regenerate the ECM [57]. Activation of the receptor for advanced glycation end products (RAGE)/$\beta$-catenin pathway under high-glucose conditions suppresses tenogenic differentiation while promoting osteogenic shifts, thereby favoring pathological remodeling [58]. Similarly, hypercholesterolemia induces TSPC apoptosis and autophagy in vitro, with ROS-mediated Protein Kinase B (AKT)/Forkhead box protein O1 (FOXO1) signaling suppressing key tendon genes such as Scx and Tnmd [59] (Fig. 2).

Fig. 2.

Systemic metabolic dysregulation and impaired ECM restoration compromise ATFP/ATLA function. Hyperglycemia activates the receptor for advanced glycation end products (RAGE)/$\beta$-catenin pathway, inhibiting TSPC differentiation and promoting pathological osteogenic transition. Elevated glucose also induces mitochondrial dysfunction and ferroptosis in tendon progenitor cells, impairing ECM regeneration. In hypercholesterolemia, ROS-mediated Protein Kinase B (AKT)/Forkhead box protein O1 (FOXO1) activation suppresses scleraxis (Scx) and tenomodulin (Tnmd) expression, disrupting ECM homeostasis. Collagen imbalance exacerbates dysfunction, with reduced type I collagen (COLI) weakening tensile strength while excessive type III collagen (COLIII) deposition promotes scarring. Impaired TSPC repair capacity and fibroblast dysfunction further contribute to cellular damage and failed ECM restoration (Created in BioRender. (2025) https://BioRender.com/tfr9sp7).

The efficacy of pharmacological modulation of inflammatory signaling has been demonstrated in experimental tendinopathy models. This is consistent with the idea that inflammation regulates matrix turnover rather than being the sole driver of disease. Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, attenuate JNK/signal transducer and activator of transcription 3 (STAT3) signaling and have been reported to reduce inflammation, scar formation, and the risk of re-rupture in injured tendons [63]. Beyond conventional NSAIDs, pristimerin—a quinone methide triterpenoid—has shown superior efficacy to indomethacin in preclinical tendinopathy models by enhancing biomechanical recovery and suppressing inflammation through absent in melanoma 2 (AIM2) inflammasome–PYCARD/apoptosis-associated speck-like protein (ASC) modulation via selective autophagy [64, 65]. Moreover, most studies are based on animal models or small-scale human trials. Large randomized controlled trials (RCTs) to confirm the efficacy of NSAIDs in pelvic tendinopathy are still lacking.

Despite these encouraging mechanistic findings, their relevance to pelvic tendinopathy remains uncertain. Long-term use of NSAIDs can prolong the time needed for tendons to heal, and may also cause problems in other parts of the body. Most studies supporting the use of NSAIDs are based on animal experiments or on small numbers of people.

Oxidative stress worsens degeneration after mechanical injury, which is why antioxidant treatments are useful. Agents such as dehydroepiandrosterone and ROS scavengers protect tendon cells from damage and reduce calcium accumulation in experimental tendinopathy models [61]. However, most supporting studies rely on animal models or limited human cohorts rather than pelvic-specific randomized trials.

Oxidative stress acts as an amplifier of degeneration once mechanical injury has occurred, providing a rationale for antioxidant-based interventions. Agents such as dehydroepiandrosterone and ROS scavengers protect tenocytes from oxidative damage and reduce ectopic calcification in experimental tendinopathy models [55]. Epigallocatechin gallate has been shown to mitigate oxidative injury, prevent non-tumorigenic differentiation, and promote ECM repair. However, its effects are dose-dependent, and a high concentration may actually inhibit tenocyte proliferation [66]. These observations underscore the challenge of attenuating pathological ROS accumulation without disrupting the physiological redox signaling required for normal repair processes [67].

A multi-center study found that physical labor, vaginal delivery, diabetes, and a family history of POP were all important factors in weakening of the pelvic floor muscles. On the other hand, PFMT and sexual activity were found to have a protective effect [68]. Mechanical loading represents another non-pharmacological lever with dual effects on tendon biology. Excessive or poorly distributed loading promotes degeneration, whereas controlled mechanical stimulation supports collagen alignment and matrix reorganization [69]. Mechanical loading is another way to treat tendon problems without using drugs. It has two effects on tendon biology. Too much or too little loading can cause problems, but controlled mechanical stimulation can help to align collagen and reorganize the matrix [69]. The interaction between yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and other proteins is important for maintaining chromosome structure and preventing chromosome breakage under stress [42]. Non-surgical rehabilitation remains the most important treatment, and new methods such as percutaneous needle electrolysis have been reported to activate the NOD-like receptor family, pyrin domain containing protein 3 (NLRP3) inflammasome and stimulate collagen-mediated regeneration in experimental studies [70].

However, the optimal loading parameters for pelvic tendinopathy—including intensity, frequency, and duration—have yet to be defined. The application of too much pressure on the pelvic floor can worsen degeneration, but the application of insufficient pressure could mean that it takes longer to recover [71]. Personalized mechanotherapy, possibly guided by imaging or sensor feedback, is a promising yet underexplored strategy.

The two strategies that aim to repair torn tendons are ‘regenerative’ and ‘molecularly targeted’. Both aim to repair the tissue around the torn tendon and to restore cell function within the tissue. However, with regard to degeneration of the Achilles tendon fascicle, these methods are still largely in the experimental stage. Consequently, the discussion here is confined to their mechanistic relevance and biological feasibility, rather than clinical endorsement. It is important to note that most regenerative concepts have been developed in non-pelvic tendon systems, where the loading environment, tissue geometry, and repair constraints differ substantially from those of the pelvic floor.

Cell-based strategies have primarily focused on increasing matrix synthesis and preserving tenogenic cell populations. TSPCs contribute to the restoration of the ECM by depositing collagen and fibronectin at injury sites [72]. Encapsulating TSPCs within ECM-mimetic hydrogels enhances cell retention and activates transcriptional programs linked to repair and matrix organization [73]. Similarly, adipose-derived mesenchymal stem cells (ADMSCs) and their extracellular vesicles have demonstrated the capacity to improve biomechanical properties, reduce apoptosis, and restore mitochondrial function in oxidatively stressed tendon models [74]. However, donor age, cell heterogeneity, and variability in delivery systems can all markedly influence outcomes, highlighting the need for rigorous standardization [74]. Furthermore, subcellular mechanisms, such as the transfer of mitochondria from mesenchymal stem cells to tenocytes, demonstrate how cell-based interventions can enhance survival without directly inducing regeneration [75]. Although a systematic review of 11 clinical studies reported architectural improvement in injured tendons following cell therapy [76], pelvic-specific evidence is still lacking, thus limiting direct extrapolation to ATFP degeneration.

Gene-based modulation offers a theoretically precise means of targeting degenerative pathways, but faces substantial translational barriers. MicroRNAs such as miR-146a have been shown to protect tenocytes from senescence through suppression of interleukin-1 receptor-associated kinase 4 (IRAK-4)/TNF receptor-associated factor 6 (TRAF6)/NF-$\kappa$B signaling [77], while miR-29a promotes ECM remodeling and tendon healing [78]. Despite these promising in vitro results, concerns remain about their efficacy, tissue effects, and side effects. There is also a lack of information regarding long-term drug safety, especially in connective tissues.

Bioactive materials and advanced delivery platforms aim to combine mechanical support with biological modulation. Scaffolds made from a type of plastic called Poly (lactic-co-glycolic acid) (PLGA) can alter macrophage behavior and help to reduce inflammation in models of tendon injury [79]. Decellularized ECM scaffolds can be adjusted according to their mechanical properties and the speed at which they break down, providing early support for tissue as it changes shape [80, 81].

Adding antioxidant or anti-inflammatory hydrogel microspheres allows control of specific stressors that depend on phase, such as oxidative and inflammatory signaling [67, 73]. Growth factor-functionalized scaffolds, including those incorporating vascular endothelial growth factor (VEGF) or platelet-derived growth factor (PDGF), enhance blood vessel formation and repair. However, too many new blood vessels may lead to scarring rather than helping the body to heal, highlighting the need for controlled blood vessel growth [82, 83].

Nanoparticle-based systems can help by releasing the drug over a longer period, reaching deeper into the tendon, and causing less tissue damage when injected [84, 85, 86]. Notably, lipid nanoparticles carrying SMAD family member 3 (SMAD3) siRNA and collagen I mRNA have shown combined antifibrotic and regenerative effects in human tenocyte models, demonstrating the potential of dual-function molecular payloads [87].

Taken together, these findings reinforce the principle that mechanical overload is the main cause of ATFP degeneration. Hormonal remodeling during the peripartum susceptibility window, along with other phase-dependent factors, then shapes the subsequent repair trajectories. Progress in this field is therefore unlikely to result from the widespread application of regenerative technologies in isolation. Instead, meaningful advances will depend on the precise alignment of intervention timing, molecular target selection, and the tissue-specific mechanical context with the underlying biology of ATFP degeneration.

Cell-, gene-, and biomaterial-based strategies can modulate ECM organization, cell survival, and inflammatory tone in experimental tendon models. However, the safety, durability, and biomechanical compatibility of these approaches in the pelvic floor, particularly in the ATFP, remain unproven. To evaluate the progression of this condition using regenerative or molecularly targeted strategies, preclinical studies with pelvic models must include physiological loading and long-term functional outcomes.

A major limitation of the current review is the heavy reliance on mechanistic evidence derived from non-pelvic tendon models, such as the Achilles tendon, or preclinical animal systems. These models provide a basic understanding of general tendinopathy. However, the way the body moves, the shape of the tissue, and the way it is repaired are very different in the pelvic floor compared to the extremities. This means that we cannot take what we learn about matrix turnover and cellular signalling in the human ATFP and just apply it elsewhere without careful thought first. The unique loading patterns and specific biological modifiers in the pelvis may significantly alter the observed degenerative pathways.

There is also a considerable scarcity of pelvic-specific human data. In particular, there is little information on longitudinal molecular and architectural transitions during the peripartum susceptibility window or throughout ageing. Prevailing clinical phenotypes, including pelvic organ prolapse and stress urinary incontinence, do not currently differentiate tendon-like connective tissue failure from broader muscular or fascial dysfunction. This lack of anatomical specificity in the clinical literature complicates the identification of the ATFP as a distinct biological substrate. It also hinders the development of clinically deployable tools for mechanism-based risk stratification, early detection, and objective monitoring of tissue condition.

A substantial translational gap persists between emerging regenerative strategies and validated clinical outcomes. Molecularly targeted approaches, including cell-based therapies, gene modulation and bioactive scaffolds, have shown promise in experimental settings. However, the long-term safety, durability and biomechanical compatibility of these approaches within the human pelvic floor remain to be proven. There is a lack of large-scale randomised controlled trials and multicentre registries in this field, which would be necessary to verify the efficacy of these interventions and establish standardised structural endpoints for repair. Without this clinical validation, many of the advanced repair strategies discussed here remain hypothetical rather than forming part of established treatment modalities.