Australian and New Zealand Journal of Obstetrics and Gynaecology 2014; 54: 198–205 DOI: 10.1111/ajo.

12169

Review Article

Recent studies of genetic dysfunction in pelvic organ prolapse: The role

of collagen defects
Veronica F. LIM,1 John K. KHOO,1 Vivien WONG1 and Kate H. MOORE1,2
1
Pelvic Floor Unit, St George Hospital/University of New South Wales, Sydney, and 2Department of Urogynaecology,
St George Hospital/University of New South Wales, Kogarah, NSW, Australia

Gynaecologists are becoming increasingly aware that women with a family history of prolapse are at an increased risk of
prolapse refractory to treatment. In the past five years, several genetic mutations have been shown to correlate with
increased prolapse susceptibility. These mutations can result in disordered collagen metabolism, which weaken the fascial
support of the pelvic organs. This review examines the contemporary evidence regarding the role of collagen in prolapse.
Key words: collagen, genetic influences, immunohistochemistry, pelvic organ prolapse.

Introduction history of haemorrhoids, varicose veins, hernias and

Pelvic organ prolapse (POP) is the herniation of viscera
into the vagina, generally associated with weakness of the
supporting structures. Prolapse is a common condition.
Recent Australian data show that the lifetime risk of a
woman having surgical treatment for prolapse in this
country is 19%.1 Prolapse is likely to become more
prevalent as our population ages, so a review of new
evidence regarding the aetiology of this condition is timely.
Aside from the traditional risk factors such as age,
parity, vaginal childbirth and increased intra-abdominal
pressure (ie obesity, chronic cough and constipation)2, the
concept of a genetic tendency towards prolapse is
becoming more apparent. For example, women with a
positive family history of POP are more likely to develop
prolapse compared to women with no family history (OR
2.58, 95% CI 2.12–3.15).3 Furthermore, twin studies have
identified that genetic factors contribute about 43% of the
variation in liability to prolapse.4
Most gynaecologists are aware of the link between
connective tissue disorders and prolapse. For example,
women who have collagen-associated disorders such as
Ehlers–Danlos syndrome and Marfan syndrome have an
increased prevalence of prolapse. Such women tend to
have more severe prolapse symptoms and are more likely
to get recurrence after vaginal repair.5–8 Women with a
Correspondence: Prof Kate H. Moore, Department of
Urogynaecology, St George Hospital/UNSW, First floor,
Pitney clinical sciences building, Kogarah, NSW 2217,
Australia. Email: k.moore@unsw.edu.au
Received 12 August 2013; accepted 16 November 2013.
abdominal striae (conditions thought to be related to
collagen deficiency) are also more likely to develop
symptomatic prolapse.9–11 Conversely, women with pro-
lapse are significantly more likely to develop hernias com-
pared with controls (31.6% vs 5%, n = 120, P = 0.002).11
There is strong evidence that collagen imbalance
contributes to the pathogenesis of hernias.12
Changes in collagen metabolism may lead to weakened
fascia, which plays an essential role in the support of the
pelvic viscera.13 For an overview of the ligamentous layers in
the pelvis, see Figure 1, which describes the three imaginary
planes, based on the level of support. Defects or decreased
vaginal wall resistance in each level may cause different
organs to prolapse.17 Over the past five years, studies have
identified several genetic variants (or polymorphisms)
implicated in prolapse. These genetic variations affect
collagen synthesis and remodelling of the extracellular
matrix (ECM). This review aims to summarise recent
findings regarding the role of collagen dysfunction and its
relation to genetic aberrations in the pathogenesis of POP.
Materials and Methods
Literature searches were performed primarily using
MEDLINE from 1996 to 2013. The MeSH terms ‘pelvic
organ prolapse’, ‘uterine prolapse’, ‘cystocele’, ‘rectocele’,
uterosacral ligament’, ‘cardinal ligament’, ‘immunohisto-
chemistry’, ‘collagen’, ‘matrix metalloproteinase’, ‘connective
tissue’, ‘extracellular matrix’, ‘fibroblast’, ‘polymorphism’,
‘genetic predisposition’ and ‘fascia’ were used and combined.
Hand-searching of reference lists of relevant main journal
articles was done to increase the search pool. A total of 30
articles were identified between 1996 and 2013. Only studies

198 © 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

The Australian and

New Zealand Journal
of Obstetrics and
Gynaecology
 Genetic dysfunction in pelvic organ prolapse

Figure 1 Current anatomical considerations for prolapse. Level 1: The upper 1/3 of the vagina is suspended to the pelvic wall by the
uterosacral and cardinal ligaments, condensations of endopelvic fascia. These ligaments provide apical support for both the uterus and
upper third of vagina. Originally thought to be purely ligamentous, these structures are actually complexes of vascular and hypogastric
nerves enveloped by connective tissue. Tissue resilience decreases with age-related atrophic change and injury.14–16 Defect: Uterine
prolapse, or vaginal vault prolapse (in hysterectomy) Level 2: The middle 1/3 of the vagina is attached laterally to the arcus tendineous
fasciae pelvis (ATFP). Anteriorly, vaginal wall is attached to the bladder via the pubocervical fascia. Defect: Cystocele (protrusion of
bladder). Posteriorly, vaginal wall is attached to rectum via the rectovaginal fascia. Defect: Rectocele (protrusion of rectum) Level 3: The
lower 1/3 of the vagina is fused to the surrounding perineal membrane and perineal body. Defect: Urinary stress incontinence.

that focussed on prolapse (not urinary stress incontinence)
were examined. Prolapse was defined as ≥ Stage 2 on POPQ
assessment.18 Studies that were included investigated the
significance of collagen changes and controlled for
confounding variables (parity, age, menopause, smoking and
BMI) during statistical analysis. Studies that included control
samples taken from patients with gynaecological malignancy,
leiomyoma or endometriosis were excluded as these were not
considered true ‘control’ patients. Therefore, a total of 22
studies were included.
Collagen composition
The connective tissue of the supporting ligaments and
vaginal wall is composed of ECM. Within this matrix,
there is a predominance of fibrillar components (collagen
and elastin), compared to nonfibrillar elements (pro-
teoglycans, hyaluron and glycoproteins). Analysis of the
cardinal ligaments reveals that 70–80% consists of
collagen.19 Collagen is thought to be one of the main
determinants of biomechanical strength. There are
approximately 28 types of collagen found in the human
body, but the main subtypes in the pelvic floor are types I
and III. Whilst collagen I confers higher tensile strength
due to its longer and thicker fibres, collagen III is more
prevalent as it provides tissue elasticity and flexibility
within the pelvis. Type III collagen is also the first type of
collagen involved in wound repair and fibrosis, before it is
replaced by collagen I.20–22 Several studies have compared
the amount of total and individual subtypes of collagen in
the supporting ligaments and vaginal tissue of women with
POP to a control group (see Table 1).19,23–36

© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists 199
V. F. Lim et al.

Studies of collagen composition in uterosacral/ collagen content between women with prolapse and the
cardinal ligament control group.24,25 These studies quantified collagen via
hydroxyproline assay – hydroxyproline is a component of
There were 8 studies that specifically analysed collagen
collagen and is thus an indirect measure of collagen levels.
components within this level 1 structure. In the uterosacral
This assay is not collagen specific and is not entirely
and cardinal ligaments of women with prolapse, most
reliable in unpurified tissue samples, with results differing
studies revealed decreased total collagen, but increased
depending on assessment methods.37
collagen III/I ratio. As collagen III is more flexible,
increased collagen III/collagen I ratio contributes to tissue
laxity and prolapse susceptibility. However, conflicting Studies of collagen composition in vaginal wall
results have arisen, partly due to the use of different
Findings in vaginal wall biopsies are also conflicting
methods of collagen assessment. Due to its molecular
(Table 1).30–34 Recently, Zhou et al.,30 found decreased
structure, collagen is notoriously difficult to quantify.21
collagen III expression (and reduced tissue elasticity) in full-
Most of the studies analysed in this review utilised
thickness samples of vaginal tissue from patients with
immunohistochemistry, a method that quantifies the
prolapse. Previous biomechanical study has also
amount of collagen through visual evaluation. The
demonstrated that women with prolapse have stiffer vaginal
subjectivity of this method, compounded by relatively
tissues.38 In contrast, Moalli et al.,31 found increased
small sample sizes within the published articles, has led to
collagen III in the subepithelial layers of the vaginal wall.
variable findings. For example, Kokcu et al.,23 found
These inconsistencies may arise from the following: (i)
increased total collagen content in the uterosacral
different methods used to assess collagen quality; and (ii)
ligaments, but did not clarify the subtype of collagen
different biopsy sites from which the collagen samples were
involved. Two other studies found no difference in

Table 1 Collagen analysis biopsy specimens of supporting ligaments and vaginal tissue in women with and without POP (in the order of
discussion of text)

Study (author, Target population Findings: women with POP vs

year, ref#) and sample size Tissue analysed Analytic method control
Kokcu 200223 24 POP women 21 Uterosacral ligaments Histological analysis ↑collagen
controls
Phillips 200524 14 POP women 14 Uterosacral ligaments Hydroxyproline assay No difference in hydroxyproline
controls levels
Suzme, 200725 14 POP women 12 Uterosacral ligaments Hydroxyproline assay No difference in hydroxyproline
controls levels
Ewies 200319 33 POP women 25 Cardinal ligaments Histology; ↑collagen III
controls immunohistochemical analysis
Gabriel 200526 25 POP women 16 Uterosacral ligaments Histomorphological and ↑ collagen III No change in
controls immunohistochemical analysis collagen I
Liapis 200127 32 POP women 28 Uterosacral ligaments Immunohistochemical analysis No change in collagen III
controls Paravaginal fascia
Vulic 201128 46 POP women 49 Uterosacral ligaments Immunohistochemical analysis ↓collagen I
controls
Yucel 201329 29 POP women 35 Uterosacral ligaments Immunohistochemical analysis ↓collagen I ↑ collagen III
controls
Zhou 201230 17 women with Anterior and posterior Western blotting ↓collagen III No change in
POP 5 controls wall collagen I
Moalli 200531 62 POP women 15 Vaginal apex (full Histological analysis ↑ collagen III
controls thickness biopsy)
Jackson 199632 8 POP women 10 Vaginal epithelium Hydroxyproline assay ↓total collagen No change in
controls collagen III/I ratio
Lin 200733 23 POP women 15 Anterior vaginal wall Immunohistochemical analysis ↓collagen III
controls
Mosier 201034 47 POP women 7 Anterior vaginal wall Quantitative real-time PCR ↑collagen I ↑ collagen III ↓collagen
controls III/I ratio
Salman 201035 10 POP women 10 Cardinal ligaments Light and electron microscopy Structural alterations in size and
controls distribution of collagen fibres
Badiou 200836 11 POP women 8 Anterior vaginal wall Histological and morphometric Structural alterations in size and
controls apex analysis distribution of collagen fibres
POP, pelvic organ prolapse; PCR, polymerase chain reaction.

200 © 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Figure 2 Layers of the vagina showing tissues obtained from
biopsies of different depths.
obtained. The amount of collagen varies according to the
layer of the vagina biopsied (adventitia, muscularis, lamina
propria and superficial stratified squamous epithelium)
(Figure 2).31
Figure 3 Schematic overview of genetic and biochemical factors governing collagen synthesis and degradation.
© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
Genetic dysfunction in pelvic organ prolapse
Collagen morphology
Collagen function is dependent on its morphology, which
can be assessed by immunohistochemistry staining. For
example, Salman et al.,35 used light and electron
microscopy to analyse connective tissue fibres in the
cardinal ligaments. He found that in women with POP,
the extracellular matrix was less dense, with sparse but
thicker distribution of collagen fibres compared to
controls. Collagen fibrils were also increased in size, with
mean diameter of 61.2  11.4 nm as opposed to
52.5  6.1 nm in women without POP (P < 0.001).
Similar biopsies of vaginal tissue from women with
prolapse showed looser dispersion of fibrils in the
muscular layer of the vaginal wall.36 Thus, alterations in
collagen morphology appear to be associated with
prolapse.
Regulators of collagen
The ECM is under a dynamic state of remodelling, a
balance of synthesis and breakdown (Figure 3). Fibroblasts
are the main synthesisers of collagen I and III, whilst matrix
enzymes called metalloproteinases (MMP) degrade
collagen. Collagen I and III are degraded by MMP-1,-2,-8,
-9 and -13. Tissue inhibitors of metalloproteinases, known
as TIMP, then inhibit the MMP, achieving a balancing
effect.21,22,39,40 Genes (ie HOXA11 and COL3A1) govern
the synthesis of these enzymes (Figure 3).
201
V. F. Lim et al.

Changes in collagen may be due to altered fibroblast
behaviour. Fibroblasts are mechanoresponsive, modifying
their actin cytoskeleton when stretched. This results in
poor contractility and decreased functionality after stretch,
as reviewed by Kerkhof et al.,20 Women with prolapse
have reduced density of fibroblasts in the uterosacral
ligaments and paravaginal fascia.23 Several studies have
also demonstrated modified fibroblast responses in
prolapse.41–44
Several authors have analysed the expression of collagen
regulators (MMP and TIMP) (Table 2). Expression of
MMP-1,-2 and -9 is increased in women with prolapse,
demonstrating more collagen breakdown with loss of tissue
integrity. Within the published body of literature,
conflicting findings have arisen. Unfortunately, authors do
not consistently study all the subtypes of MMP, and
biopsy sites also vary considerably between studies.
Regardless, these MMP all perform a common function
and are actually quite similar.
Collagen is initially degraded into fragments by MMP-
1,-8 and -13 before it is solubilised by MMP-2 and -9.21
The increased expression of any MMP indicates
accelerated remodelling and collagen degradation. MMP
are inhibited by tissue inhibitors of metalloproteinases
(TIMP), and decreased TIMP expression corresponds
with increased MMP (Figure 3).22 Recent studies have
investigated TIMP expression in relation to MMP.46,49
It is not known whether these differences in the
extracellular matrix are a cause or a consequence of injury.
Increased mechanical load overstretches connective tissue,
inducing extracellular remodelling. This activates MMP
and alters both collagen expression and fibroblast
behaviour.50,51 This cause-and-effect relationship is
extremely difficult to investigate. The duration of prolapse
is often unspecified in the prolapse cohort, and it is possible
that remodelling of the ECM has occurred in response to
the prolapse itself. The ideal solution, a large longitudinal
study in which unaffected women are biopsied and
monitored over time for prolapse, is yet to be carried out.
Two studies have attempted to address this issue by
looking at paired samples of prolapsed tissue from the
vaginal wall and nonprolapsed tissue from the cervix
within the same woman. Wong et al.,52 used
hydroxyproline assays and found that in women with
prolapse, there was significantly reduced collagen content
(P = 0.01) in the cervix compared to women without
prolapse. However, the cervix is a nonsupporting tissue
and is not susceptible to the ECM changes induced by
prolapse. Therefore, evidence presented by Wong et al. is
difficult to interpret, partly because they did not
differentiate between women with stress incontinence and
POP in their study groups. Kannan et al.,53 studied a
sample of women with prolapse, comparing biopsies of
prolapsed vaginal wall tissue to tissue that appeared
‘normal’ macroscopically. They found no difference
between the two types of tissues, both demonstrated
condensed collagen fibres upon histological analysis.
Recently, studies linking several genetic mutations to
prolapse have begun to clarify this confusing ‘cause-and-
effect’ issue.

Table 2 Analysis of MMP expression in biopsy specimens of supporting ligaments and vaginal wall of women with POP compared to
control

Study (author, Target population Findings: women with

year, ref #) and sample size Tissue analysed Analytic method POP vs control
Jackson 199632 8 POP women 10 Vaginal epithelium Immunohistochemical analysis ↑ MMP-2 ↑MMP-9
controls
Phillips 200524 14 POP women 14 Uterosacral ligaments Gelatin zymography; ELISA No change in MMP-2 No
controls change in MMP-9
Moalli 200531 62 POP women 15 Vaginal apex (full- Gelatin zymography ↑MMP-9
controls thickness biopsy)
Choy 200841 15 women with Cardinal ligaments Quantitative real-time PCR mRNA ↑ MMP-2
POP 15 controls
Strinic 200945 40 women with Uterosacral ligaments Immunohistochemical analysis ↑MMP-1 No change in
POP 14 controls MMP-2
Liang 201046 19 women with Uterosacral ligaments Immunohistochemical analysis; ↑MMP-2 ↓TIMP-2
POP 9 controls quantitative real-time PCR mRNA
Budatha 53 women with Anterior vaginal wall apex Quantitative real-time PCR, gelatin ↑MMP-9
201147 POP (vaginal muscularis) zymography
Dviri 201148 20 women with Uterosacral ligaments Immunohistochemical analysis ↑MMP-1 ↑MMP-9
POP 20 controls Vaginal tissue
Vulic 201128 46 women with Uterosacral ligaments Immunohistochemical analysis ↑MMP-1
POP 49 controls
Liang 201246 27 women with Uterosacral ligaments Immunohistochemical analysis; ↑MMP-2 ↓TIMP-2
POP 14 controls quantitative real-time PCR mRNA
POP, pelvic organ prolapse; ELISA, enzyme linked immunosorbent assay; PCR, polymerase chain reaction; mRNA, messenger
ribonucleic acid; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.

202 © 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
 Genetic dysfunction in pelvic organ prolapse

Genetic predisposition availability of genetic testing and counselling, women with

a predisposition to prolapse may be able to measure their
This is a new but promising area of research. Connell
increased risk, although the cost-effectiveness of this needs
et al.,54 demonstrated that the development of the support
to be established.
ligaments is coded by the homeobox gene HOXA11.
Furthermore, with the identification of gene
Knockout mice models (genetically modified mice with
polymorphisms associated with POP, individuals should
deleted HOXA11) are devoid of uterosacral ligaments
be able to undergo genetic screening to stratify their risk of
(Figure 3). In women with POP, expression of HOXA11
prolapse. High-risk individuals can be offered lifestyle
is decreased and linked to increased levels of MMP-2. It is
options that will lower the risk, such as the avoidance of
proposed that HOXA11 regulates the expression of genes
obesity, chronic constipation, heavy-lifting occupations
involved in extracellular matrix metabolism.55
and prolonged second stage of labour. Interventional
Allen-Brady et al.,56 used genomewide association
therapies aiming to reverse ECM changes and fibrosis can
analysis on 2976 women and identified six single nucleotide
be developed to halt POP progression. This may not be so
polymorphisms (SNP) linked to POP. SNPs are very
far in the distant future, as fibrosis regression in the liver is
common mutations, occurring when a different nucleotide
already evident following experimental drug therapy.67
is substituted for the normal nucleotide in a DNA sequence.
The direct cost of surgical treatment of POP in USA
This results in a defective protein being produced during
alone is more than $1 billion per year.68 This cost will
gene transcription and translation. These authors found
only increase, as the number of women affected by
that at least one of these mutations involves the COL181A
prolapse is estimated to double within the next thirty
gene, which is involved in type I collagen regulation.
years.69 Prevention is thus highly desirable.
Other genes may be involved in the regulation of collagen
However, it is important to note that the aetiology of
and MMP formation.57–64 Nucleotide polymorphisms in
prolapse is multifactorial with many other contributing
the COL3A1 genes are associated with prolapse, thus
mechanisms. Firstly, the impact of different racial groups
suggesting the role of defective collagen III in the genesis of
upon hereditary aspects of collagen metabolism confers
prolapse.57–59 Interestingly, type IV Ehlers–Danlos
considerable heterogeneity upon the results obtained.
syndrome is due to mutations in the same COL3A1 gene.
Furthermore, other factors, such as fascial fibre tearing,
Patients with this condition are known to have abnormal
altered skeletal anatomy, reduced levator ani tone due to
collagen III, which causes fragile tissues and poor wound
neuronal damage and levator ani avulsion following
healing.65 However, an association between nucleotide
childbirth, may also contribute to prolapse
polymorphism in COL1A1 (the gene which codes for
development.2,70,71 Levator avulsion defect is the traumatic
collagen I) and prolapse has not yet been proved.60,61
muscle detachment of the puborectalis muscle from its
A mutation in the gene expressing MMP is also
insertion on the inferior pubic rami. This injury occurs in
associated with prolapse.62–64 Chen et al.,62 conducted a
up to 36% of women72 and has been shown to be associated
case–control study in Taiwanese women with prolapse
with prolapse, particularly in the anterior and central
(n = 92) versus control (n = 152). The authors found that
compartment.70 More recently, levator avulsion defects
two genetic polymorphisms of MMP-9 were significantly
have also been found to be strongly associated with
associated with prolapse risk (OR: 5.41 and 5.77). These
recurrent pelvic organ prolapse after prolapse repair.73–75 It
findings contradict the results of an Italian study,64 which
is likely that the conflicting results in the published literature
found no difference in MMP-9 expression between the
on the association between collagen and prolapse aetiology
prolapse and the control groups. However, there was a
are complicated by the presence of major anatomical
positive association between a single variation of MMP-1
trauma related to childbirth, as these factors are often not
and prolapse. These trends support the hypothesis that
taken into account and controlled for during the assessment
increased extracellular matrix remodelling contributes
of collagen integrity. Potential ways to reduce this
towards prolapse. It is important to note that current
confounding bias include limiting the study population to
studies are limited as they tend to focuss on one particular
nulliparous women only and incorporating diagnosis and
ethnic group at a time. In the future, evaluation of a large
assessment for levator avulsion.
variety of genetic groups may be possible.
Further research is required in all directions in order to
The evidence that collagen changes are involved in
integrate our knowledge of the various components of
prolapse continues to grow. Currently, genes investigating
prolapse aetiology. However, patients and gynaecologists
components other than collagen in the extracellular matrix
are becoming increasingly aware that biochemical and/or
are being investigated. These include genes coding for
genetic defects in collagen metabolism may have a role in
elastin metabolism and smooth muscle, as reviewed by
a selected subgroup of women with prolapse.
others.39,66

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