The role of collagen and its association with female pelvic organ prolapse.

Female pelvic organ prolapse (POP) is a common condition, with a 19 per cent lifetime risk of a woman requiring surgical treatment in Australia.1 Multiple risk factors for prolapse development have been described over the years, including age, parity and vaginal childbirth, with its associated pelvic floor trauma such as levator avulsion.2 More recently, the focus has shifted towards correlation with genetic traits and underlying connective tissue disorders.

A patient with a family history of POP is two-to-three times more likely to develop prolapse than a patient with a negative family history.3 Likewise, women with collagen-associated disorders – such as Marfan syndrome or Ehlers-Danlos syndrome – are more likely to present with greater stages of prolapse and higher risks of prolapse recurrences.4 It has been shown in a population-based cross-sectional study the odds ratio (OR) of 1.8 for a positive association with symptomatic prolapse in women with a history suggestive of deficient connective tissue.5 These patients may present with clinical features of connective tissue dysfunction such as varicose veins, hernias and haemorrhoids.

Alteration in collagen synthesis and metabolism has been thought to contribute to defective fascia, thus compromising pelvic organ support.6 Within the connective tissue of supporting ligaments and the vagina is an intricate network of fibrillar components, such as collagen and elastin, as well as non-fibrillar components, such as proteoglycans, hyaluron and glycoproteins. Together, these form the extracellular matrix (ECM). The ECM undergoes a constant remodelling process; synthesis of collagen by fibroblasts and degradation by matrix metalloproteinase (MMPs), which can be inhibited by tissue inhibitors of metalloproteinases (TIMPs).

There are approximately 28 types of collagen within these matrices, with the main subtypes being Type I to Type V. Subtypes more commonly found in the pelvic floor are Type I, which are longer and thicker fibres providing strength, such as those found in ligaments, while Type III collagen contributes to tissue elasticity, often found within fascia and skin. Several studies have ooked at ratios of Type I to Type III collagen in supportive pelvic structures, such as uterosacral and cardinal ligaments of women with POP. Unfortunately, data on collagen quantification in these structures have been conflicting as methods of assessing collagen morphology, deciding appropriate sites to biopsy as well as the small sample population studied have all contributed to the heterogeneity. Nonetheless, the overall trend found in most studies have showed a general reduction in total collagen with an increase in the Type III to I ratio, suggesting increased tissue laxity and poor tissue integrity in women with prolapse.

The balance of synthesis and metabolism of collagen involves activity of fibroblasts, elastin and collagen regulators such as the MMPs and TIMP. Collagen fibroblasts alter their actin cytoskeleton when under load thus resulting in poorer function when stretched.7 In fact, Kokcu et al8 have found reduced density of fibroblasts in the uterosacral ligaments and paravaginal fascia in women with prolapse. Elastin is another component found within the ECM, responsible for tissue elasticity and recoil of tissue across all organs of the body. Tissue strength is reliant on the integrity of the elastin and collagen fibre crosslinks. There appears to be a general trend towards decreased level of elastin in the pelvic tissue of women with prolapse.9

As opposed to fibroblasts and elastin, an increased MMP expression indicates an accelerated remodelling and collagen degradation process. There are several types of MMP, with expression of MMP 1, 2 and 9 being increased in women with prolapse. It is not known, however, whether these alterations in the ECM are the result of injury caused by increased load on these structures or an intrinsic condition leading to tissue laxity and prolapse. The cause-and-effect relationship is difficult to investigate, especially since many of these studies are on women with prolapse. An ideal study to quantify the natural history of collagen dysfunction and its association with prolapse would be to biopsy unaffected women and monitor over time for prolapse.

Genetic predisposition

In the last five years, there has been a growing research interest in identifying genetic variance implicated in POP. Several gene mutations have been linked to abnormal extracellular matrix remodelling and associated prolapse development. It appears genes such as HOXAII and COL3A1 govern the synthesis of MMP enzymes. Changes or alteration in the genetic coding can affect the regulated function of these MMPs. Mutation in the gene expressing MMP was seen in a study on Taiwanese women with prolapse compared to control. In that study, Chen et al found that women with MMP genetic polymorphism had higher risks of prolapse with an OR 5.41 and 5.77.10 Connell et al demonstrated that the HOXAII gene coded for uterosacral ligament development.11 In genetically modified mice models where the HOXAII gene was deleted, there was an absent of uterosacral ligament development. Hence it was postulated that the HOXAII gene regulates the metabolism of extracellular matrix, and it appears that the HOXAII gene expression is reduced in women with POP.

Other genes involved are those of COL3A1, COL181A and COL1A1. Nucleotide polymorphisms in the COL3A1 genes have been found to be associated with prolapse6, which may suggest the association between these gene mutations and that of defective collagen structure. This is evident in patients with Type IV Ehlers-Danlos syndrome who have COL3A1 gene mutations. These patients often present with more severe and difficult to treat POP, poorer tissue quality and compromised wound healing.

Clinical implication

The aetiology of prolapse is multifactorial and patient education is paramount. The ability to provide as much information on factors that can increase the risk of prolapse development and prolapse recurrence is useful for patient counselling. Unfortunately, to date, the availability of such genetic testing in Australia has been limited, however, it may become more accessible with increased demand by informed clinicians. Increased knowledge of the genetic disorders currently linked to prolapse development means patients with clinical features of a connective tissue disorder can be screened prior to prolapse treatment and warned of the possible increased risk of failure with surgical intervention.