Medical Hypotheses 104 (2017) 97–100

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Platelet rich plasma as a minimally invasive approach to uterine

prolapse
E.L. Chrysanthopoulou a,b,⇑, V. Pergialiotis a, D. Perrea a, S. Κourkoulis c, C. Verikokos a,d,
S.K. Doumouchtsis a,e,f
a
Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, National and Kapodistrian University of Athens, Greece
b
Department of Obstetrics and Gynaecology, Queen’s Hospital, Rom Valley Way, Romford, Essex, United Kingdom
c
National Technical University of Athens, Greece
d
2nd Department of Surgery, Vascular Surgery Unit, Laiko General Hospital, Medical School of Athens, Greece
e
Department of Obstetrics and Gynaecology, Epsom and St Helier University Hospitals NHS Trust, United Kingdom
f
St George’s University of London, London, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Pelvic organ prolapse (POP) is a major health problem that affects many women with potentially severe
Received 18 December 2016 physical and psychological impact as well as impact on their daily activities, and quality of life. Several
Accepted 24 May 2017 surgical techniques have been proposed for the treatment of POP. The FDA has published documents that
refer to concerns about the use of synthetic meshes for the treatment of prolapse, in view of the severe
complications that may occur. These led to hesitancy in use of these meshes and partial increase in use of
Keywords: other biological grafts such as allografts and xenografts. Although there seems to be an increasing ten-
PRP
dency to use grafts in pelvic floor reconstructive procedures due to lower risks of erosion than synthetic
Uterine prolapse
Uterosacral ligaments
meshes, there are inconclusive data to support the routine use of biological grafts in pelvic organ prolapse
Platelet rich plasma treatment.
In light of these observations new strategies are needed for the treatment of prolapse. Platelet rich
plasma (PRP) is extremely rich in growth factors and cytokines, which regulate tissue reconstruction
and has been previously used in orthopaedics and plastic surgery. To date, however, it has never been
used in urogynaecology and there is no evidence to support or oppose its use in women who suffer from
POP, due to uterine ligament defects. PRP is a relatively inexpensive biological material and easily pro-
duced directly from patients’ blood and is, thus, superior to synthetic materials in terms of potential
adverse effects such as foreign body reaction. In the present article we summarize the existing evidence,
which supports the conduct of animal experimental and clinical studies to elucidate the potential role of
PRP in treating POP by restoring the anatomy and function of ligament support.
Ó 2017 Elsevier Ltd. All rights reserved.

Introduction
Prolapse is a common condition that is the result of progressive
weakening of the supportive structures of the uterus. It is esti-
mated that approximately thirty per cent of women over the age
of 50 have uterine prolapse [1]. In the U.S. nearly 200,000 women
undergo surgery for prolapse annually, with a cost that exceeds
one billion dollars [2]. Every woman has an 11.1% lifetime risk of
undergoing surgery for uterine prolapse, until the age of 80 years
⇑ Corresponding author at: Laboratory of Experimental Surgery and Surgical
Research N.S. Christeas, University of Athens, Greece.
E-mail address: e.chrysanthopoulou@gmail.com (E.L. Chrysanthopoulou).
[3]. Scientists estimate that in the next 30 years there will be an
increase by 45% in women who seek treatment for prolapse.
The dysfunction of ligaments that support the uterus is multi-
factorial. Specifically, current evidence suggests that the duration
of labour, the neonatal birthweight and parity are independent fac-
tors that increase the risk of uterine prolapse [4,5]. Chronically
increased intra-abdominal pressure is also triggered by conditions
such as obesity, chronic bronchitis, bronchiectasis, asthma and
constipation and may affect the integrity of the pelvic floor.
Besides, the transition to menopause alone is associated with uro-
genital atrophy, which results in ligament atrophy, relaxation of
the pelvic floor and uterine prolapse, while it appears that the inci-
dence of prolapse increases with age [6].

http://dx.doi.org/10.1016/j.mehy.2017.05.018
0306-9877/Ó 2017 Elsevier Ltd. All rights reserved.
98 E.L. Chrysanthopoulou et al. / Medical Hypotheses 104 (2017) 97–100
Prolapse is a condition that affects quality of life, with implica-
tions in psychology, self-esteem, sexual and social life. As the aver-
age life expectancy of women increases, more and more women
will seek medical assistance for prolapse repair. In this context, it
seems that the introduction of new therapeutic modalities in the
field becomes urgent.
Various surgical techniques have been used for the treatment of
prolapse, with recurrence rates up to 30% [3]. Vaginal meshes have
been widely used in recent years, but due to the high rates of com-
plications [7], the FDA published reports informing patients and
physicians about the complications that accompany their use and
underlined the importance of investigating innovative methods
for the treatment of prolapse [8].
The hypothesis
The uterosacral (USL) and cardinal ligaments (CL) provide sup-
port to the uterus and pelvic organs, and the round ligaments (RL)
maintain their position in the pelvis. In women with pelvic organ
prolapse (POP), the connective tissue, smooth muscle, vasculature,
and innervation of the pelvic support structures are altered [9].
Both laparoscopic and vaginal procedures that involve USL suspen-
sion have been developed and widely used, but complications have
been reported, usually secondary to their proximity to the ureter,
vessels, rectum and sacral nerve roots [10].
An alternative approach for the management of prolapse could
be the implementation of an injectable agent, which could primar-
ily enforce the ligaments. This regenerative principle with autolo-
gous substances could potentially limit the side effects of
synthetic materials. Interestingly, fibrin adhesives and PRP have
been used in various fields in the past 30 years [11], but the sub-
stances have not been used for treatment of urogynaecological
problems.
Research projects investigating the regenerative abilities of
plasma offer options of using an autologous substance with adhe-
sive, healing, and haemostatic properties at low cost [12–14].
In this context, injecting an autologous adhesive factor to the
ligaments might have promising, results in the treatment of POP,
by enforcing the ligaments and restoring normal anatomy, with
minimal, if any, complications.
Confirmation of the above beneficial effects of PRP will provide
the necessary knowledge for the design and conduct of clinical
studies aimed for the reinforcement of USL. The purpose of this
article is to summarize available evidence in the field and construct
a robust hypothesis, which could potentially drive the research
agenda towards conducting experimental and clinical studies in
this field.
Current evidence
Uterosacral ligament
The USL plays an important role in pelvic organ support, and is
used as corrective support in pelvic reconstructive surgery [15,16].
In a 15-month follow up women after modified high uterosacral
ligament suspension (HUSLS) women report excellent objective,
subjective and sexual function [17], and a 5 year follow up with
only 8/42 women having recurrence of vault prolapse [18].
It was previously thought that the USL consists only of connec-
tive tissue, but a study that focused on the proximal to the cervix
part of the USL showed that it also consists from smooth muscle
cells [19]. Another study by Ramanah et al. suggested that USL is
a ligamentous complex, which encompasses the inferior hypogas-
tric plexus, the hypogastric nerves and vascular elements, which
are surrounded by a fine connective sheath [19].
A previous study suggested that patients with POP have an
intrinsic deficit of a gene responsible for the development of the
USL [20]. In the USL of women with POP, there is higher expression
of collagen III and matrix metalloproteinase 2 (MMP-2) [21,22]. It
is known that collagen III plays role in tissue elasticity and exten-
sibility, therefore can be responsible for the tissue laxity in these
patients.
Biomechanics
Data concerning the biomechanical properties of USL, especially
from human live tissue are scarce in the literature. Martins et al.
observed that the maximum stress value of prolapsed vaginal tis-
sue was significantly higher compared to values from previous
studies (3-8 MPa vs 0.27–0.42 MPa) [23–25]. In another study on
fresh female cavaders, researchers showed that the USL is more
rigid than the round and broad ligaments [26]. Studies on USL in
an experimental animal model showed that hormone replacement
(using conjugated equine estrogens plus medroxyprogesterone
acetate (CEE/MPA), or ethinyl estradiol plus norethindrone acetate
(EE/NA)) increases the tensile stiffness in USL [27].
PRP and ligament healing
After tissue injury is established, platelets are the first that
arrive at site and trigger the early inflammatory phase of the heal-
ing process [28]. They help with homeostasis, through cell mem-
brane adherence, aggregation, clot formation, and release of
substances that promote tissue repair and that affect the reactivity
of blood vessels and blood cell types involved in angiogenesis and
inflammation [29,30]. PRP contains several growth factors (GFs)
that contribute to the pathophysiology of ligament reconstruction
including VEGF, IGF-I, PDGF, HGF, TGF-b and FGF [31–34]. Besides
that, platelets also contain antibacterial and fungicidal proteins,
metalloproteinases, coagulation factors, and membrane glycopro-
teins, which may affect the inflammation process by inducing the
synthesis of other integrins, interleukins, and chemokines [35].
Although many GFs are associated with wound healing, PDGF
and TGF-b 1 appear to be two of the more integral modulators
[36]. More specifically, TGF-b seems to be active in every stage of
tendon healing as it stimulates cell migration, regulates the pro-
duction of proteinases and collagen. After tissue injury, the expres-
sion of TGF-b mRNA rapidly increases and seems to suppress
matrix metalloproteinases production and to increase the synthe-
sis of extracellular matrix [37]. Separate analyses of GFs in PRP
have shown significant increases in PDGF, VEGF, TGF-b1, and
EGF, compared with their concentrations in whole blood [38–42].
However, there are conflicting results with regard to IGF-I [38–
41,43].
Platelet derived growth factor is essential in early wound heal-
ing (during the acid tide) [44,45]. Several studies support that a
single injection of PDGF significantly enhances tendon repair
[46–48].
Insulin-like growth factor-I (IGF-I) is also important for wound
healing and tissue repair. It has been proposed that systemic
administration of IGF-I with or without growth hormone enhances
healing of collagenous tissue, by increasing maximum force, ulti-
mate stress, and elasticity in biomechanical tests [49].
Animal models
There is little information regarding the biomechanics of pelvic
floor on humans, because of the difficultly of performing con-
trolled, longitudinal studies in human patients along with ethical
issues. Animal models, on the other hand, afford the opportunity
to test hypotheses more rigorously in a controlled environment.
 E.L. Chrysanthopoulou et al. / Medical Hypotheses 104 (2017) 97–100
The rabbit model has different anatomy from the humans. Its
vagina consists of two parts, an intra-abdominal cephalad portion,
which is roughly twice as long as the caudal/retroperitoneal exter-
nal portion. Rabbit has been used in studies evaluating prolapse
meshes applied to the external posterior vagina using anatomical,
histological, biochemical and biomechanical outcomes [50].
Non-human primates are considered to be the experimental
model for pelvic organ prolapse that is most similar to humans
[51,52]. Studies on squirrel monkey focus mainly on the levator
ani muscle and prolapse effects [53–57], and rhesus macaque has
been used to evaluate the impact of meshes in prolapse [58–61].
In a study of ovariectomized macaque monkeys, the use of selec-
tive oestrogen receptor modulators seems to decrease tensile stiff-
ness in USL [62].
A recent study in ovariectomized rats looked at the biomechan-
ical properties of the uterine supportive tissue as a complex, and
found that the use of selective oestrogen receptor modulators is
not improving the ultimate load and stiffness [63].
Implications for future research
PRP contains several growth factors that have been implicated
in collagenous tissue healing. Previous studies suggested that PRP
might actually enhance tendon and ligament healing. To date,
however, it has not been used as a treatment alternative for uterine
prolapse. Taking in mind the fact that the disease is primarily owed
to defective USL, it would be prudent to suggest that studies in
experimental animal models and consecutively in humans are
needed to provide new evidence. Animal experimental models
have been already studied in research protocols on prolapse, look-
ing at the biomechanical properties of defective tissue. The use of
PRP on this defective tissue can play a key role to the regeneration
of USL, as it modulates tissue healing. It is our belief that given the
limitations of current surgical strategies in prolapse surgery, the
minimally invasive approach of PRP injection in the USL deserves
at least further investigation.
Conclusion
Platelet rich plasma has healing properties that are triggered by
the abundance of growth factors and cellular elements, which are
involved in the healing process. Its use in tendon healing has been
supported from several studies in orthopaedics and plastic surgery.
However, to date, its potential use for the treatment of uterine pro-
lapse has not been investigated. Given the limitations of surgical
treatments in prolapse, future studies should investigate the
impact of PRP injection on USL to evaluate its efficacy as a mini-
mally invasive procedure.
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