Uses of prp in different gynecological disorders

Platelet Rich Plasma Implementations
in Gynecology: An Appraisal of Theory
and Practice
Ayman Shehata Dawood
Tanta University

History of PRP
• PRP has been investigated since the early 1990s and is
not ‘new;’ use of autologous PRP was first used in 1987
by Ferrari et al. [Sampson, Gerhardt, Mandelbaum.
Platelet rich plasma injection grafts for musculoskeletal
injuries: a review. Curr Rev Musculoskelet Med. 2008
Dec;1(3-4):165-74]
• Today, we know that PRP has the potential not only to
improve hemostasis, but also to contribute greatly to the
biological affect on wound healing.
• Several advancements in this innovative area of therapy
are growing at rapid pace with the procedure gaining
traction.

History of PRP
• The disciplines of, including but not limited to, plastic
surgery, dentistry, musculoskeletal, ENT, spinal and
gynecology all use PRP therapy to deliver growth factors
to optimize healing in their patients.
• In the United States, it is estimated to be used in
Obstetrics & Gynecology specifically in more than
100,000 cases annually
[Stammers, Trowbridge, Marko, Woods, Brindisi, Pezzuto,
Klayman, Fleming, Petzold. Autologous Platelet Gel: Fad
or Savoir? Do We Really Know? The Journal of
ExtraCorporeal Technology. 2009;41:P25–P30].

Platelet rich plasma
Autologous Platelet-rich plasma (PRP) is derived from
whole blood of the same individual centrifuged to remove
red blood cells. The remaining plasma has a higher
concentration of growth factors 5-10 folds greater than
whole blood.

Platelet rich plasma
The theory beyond this modality of treatment was derived
from natural healing processes as the body’s first response
to tissue injury is to deliver platelets to the injured area.
Platelets promote healing and attract stem cells to the site of
injury.
From basic science to clinical practice, PRP Injection was
applied in diseased ligaments, tendons, and joints with
marvelous repair results.

PRP Preparation
Preparation of PRP is an office procedure that involves
withdrawal of blood, preparation of the PRP, and then
injection into diseased area by the following steps:

• Venous blood (15-50 ml) is withdrawn from the patient's
arm in anticoagulant containing tubes.
• The recommended temperature during processing is
21°C-24°C to prevent platelet activation during
centrifugation of blood.
• The blood is centrifuged at 1200 rpm for 12 minutes.
• The blood separates into three layers: an upper layer
which contains platelets and WBC, an intermediate thin
layer (the buffy coat) which rich in WBCs, and a bottom
layer which contains RBCs.
PRP Preparation

• The upper and intermediate buffy layers are transferred to
an empty sterile tube. The plasma is centrifuged again at
3300 rpm for 7 minutes to help in formation of soft
pellets (erythrocyte-platelet) at the bottom of the tube.
• Discard the upper 2/3 portion of plasma as this volume is
PPP (platelet-poor plasma).
• Pellets are homogenized in lower 1/3rd (5 ml of plasma)
to create the PRP (Platelet-Rich Plasma).
PRP Preparation

• PRP is now ready for injection. Nearly 30 ml of venous
blood yields 3-5 ml of PRP.
• Clean the affected area with disinfectant before injection
of PRP.
• Assurance and discussion with patients make the
injection easier and less painful.
• PRP stimulates series of biological responses, and the
injection site may get swollen and painful for about 3
days.
PRP Preparation

PRP types
Types of PRP preparations
After centrifugation of whole blood, four preparations can
be obtained as shown in table 1. These types or
classifications were proposed by Ehrenfest et al. (2009),
depending on their cell content and fibrin density

Preparation Acronym Leucocytes Fibrin density
Pure Platelet-Rich Plasma P-PRP Poor Low
Leucocyte- and PRP L-PRP Rich Low
Pure platelet-rich fibrin P-PRF Poor High
Leucocyte- and platelet-rich
fibrin
L-PRF Rich High

• Platelets contain high concentrations of cytokines and growth
factors stored within the α-granules.
• These growth factors include platelet derived growth factor
(PDGF), insulin like growth factor (IGF 1 & IGF 2), vascular
endothelial growth factor (VEGF), platelet derived
angiogenic factor (PDAF), transforming growth factor beta
(TGF-β), fibroblast growth factor (FGF), epidermal growth
factor (EGF), connective tissue growth factor (CTGF) and
interleukin 8 (IL 8).
• In addition to growth factors (GFs), platelets contain other
substances such as fibronectin, sphingosine 1-phosphate,
etc…) which initiate wound healing.
PRP composition

The 7 important growth factors

Activation of platelets triggers release of these growth
factors by a variety of substances or stimuli such as calcium
chloride, thrombin or collagen.
PRP activation

PRP proposed mechanisms of action
The mechanisms of PRP are not exactly clear,
but laboratory studies have shown that the
increased concentration of growth factors in
PRP can potentially speed up the healing
process.
PRP Mechanism of action

Growth factors promote wound healing by initiation of the following stages:
• Resolution,
• Chemotaxis,
• Cell regeneration,
• Cell proliferation and migration,
• Extracellular matrix synthesis,
• Remodeling,
• Angiogenesis,
• Epithelialization

PRP is superior to recombinant human growth factor in the
release of multiple growth factors and differentiation factors
upon platelet activation.
Recently, the fibrin framework present over platelets was found
to support regenerative matrix leading rapid morphologic and
molecular configuration of wound healing.

PRP in Gynecology
• Though fewer articles are published on the use of
autologous platelet growth factor applications to
support wound healing and tissue regeneration
specific to gynecology versus other clinical areas,
PRP is not new to our discipline.

PRP uses in gynecology
Surgical outcomes
Vulvar / Cervical lesions
Urogynecology / Genital prolapse
Reproductive medicine
Aesthetic gynecology
Obstetrics

PRP in Surgical outcomes
postoperative pain
• Phase I/II trial of autologous platelet tissue graft in gynecologic surgery
designed to evaluate toxicity and efficacy on decreasing pain was conducted
of 55 consecutive patients undergoing gynecologic surgery, matched with 55
patients from the previous 6 months.
• Results from this study revealed median pain on the day of surgery (2.7 -
mild) in the autologous platelet tissue graft group vs. 6.7 (severe) in the
control group.
• Likewise, pain on postoperative day 1 was 2.1 (mild) in the autologous
platelet tissue graft group vs. 5.5 (moderate) in the control group. Median of
morphine per hospital stay for the autologous platelet tissue graft group was
17 mg (range 1-98 mg) vs. 26 mg (range 3-90 mg) in the control group,
which was statistically significant at p=.02.
• Importantly, there were no adverse effects associated with autologous platelet
tissue graft, and patient pain was significantly reduced

Shackelford et al. conducted a double-blind, randomized,
placebo-controlled trial using recombinant growth factor to
treat and study the effects on wound healing. The patients in
the placebo group closed 54 +/- 26 days post-operatively,
whereas wounds of patients in the treatment group closed in 35
+/- 15 days (P =.05).
That preliminary study also suggested that topical application
of 0.01% recombinant human PDGF gel accelerated healing of
separated surgical wound significantly
[Shackelford, Fackler, Hoffman, Atkinson. Use of topical
recombinant human platelet-derived growth factor BB in
abdominal wound separation. Am. J. Obstet. Gynecol., 2002,
186(4), 701-704].
wound healing

Tehranian et al, (2016) tested PRP in wound healing of high-risk
women undergoing cesarean sections. They applied PRP in 70
patients and compared them with 71 control cases without PRP
application. The inclusion criteria were body mass index (BMI) >
25, prior cesarean section, diabetes, twin pregnancy, use of
corticosteroid medication and anemia.
They found that greater reduction in the edema ecchymosed
discharge approximation (REEDA) score compared to the
control group (85.5% reduction in the PRP group; 72% in the
control group) (P < 0.001).
They concluded that PRP is an effective therapeutic approach for
wound healing, and faster wound healing is expected due to the
presence of more platelets and growth factors.
wound healing

Morelli et al, (2013) conducted a retrospective study on cases after surgery for cancer
vulva (Radical vulvectomy).
The aim of their study was to evaluate the efficacy of platelet gel application in women
after radical surgery. They divided patients into 2 groups; group A (n=10) who had
platelet gel placed during reconstructive surgery and group B (n=15) who undergone only
surgical strategies.
They found significant decrease in wound infection (P = 0.032), necrosis of vaginal
wounds (P = 0.096), and breakdown wound (P = 0.048) rates in group A compared to
group B. They also found that reduction in postoperative fever rate, hospital stay, and
faster wound healing were also detected in group A treated by PRP gel.
They concluded that platelet gel application before vulvar reconstruction represents an
effective strategy to prevent wound breakdown after local advanced vulvar cancer
surgery.
wound healing

Surgical outcomes
Obstetrics
√

PRP in Vulvar / Cervical lesions
Vulvar dystrophies
PRP was tried in many dermatological and autoimmune conditions non-responsive to
corticosteroids such as Lichen sclerosus (LS) and eczema. Lichen sclerosis affects vulva and
causes extensive scarring with progressive loss of the labia minora, sealing of the clitoral
hood, and burying of the clitoris. Lichen sclerosus causes progressive pruritus, dyspareunia,
or genital bleeding. LS has a considerable impact on quality of life of affected patients by
disturbing physical activity, sexual pleasure, and causing emotional and psychological
effects.
This condition is treated by topical and systemic corticosteroids. Application of PRP in
resistant cases of Lichen sclerosus to steroid therapy was tried by Willison et al, (2016) in
28 patients with LS. They injected PRP in vulva in fanning pattern. Patients received 3 PRP
treatments 4 to 6 weeks apart and again at 12 months.
They found that nearly all patients exhibited clinical improvement in the size of their lesions
and in 28.6% of patients lesions disappeared completely after treatment with PRP. Minimal
pain and zero complications also were reported.
They concluded that PRP injection of PRP can therefore be considered effective therapy for
LS.

Hua et al, (2102) conducted a randomized clinical study to compare the
effectiveness of autologous platelet-rich plasma (PRP) applications to laser in the
treatment of benign cervical ectopy. They applied RPP twice on the cervical
erosion with a 1-week interval in 60 patients while Laser was applied in the other
60 patients.
They found that the complete cure rates were 93.7% for the PRP and 92.4% for
the laser group (P>0.05). The mean time to re-epithelialization was significantly
shorter in the PRP (P<0.01). The rate of adverse treatment effects (i.e. vaginal
discharge or vaginal bleeding) was much lower in the PRP than in laser group
(P<0.01).
They concluded that autologous PRP applications appear promising for the
treatment of cervical ectopy in symptomatic women, as they generate a shorter
tissue healing time and milder adverse effects than laser treatment.
PRP in Vulvar / Cervical lesions
Cervical ectopy

Surgical outcomes
Obstetrics
√
√

Mongardini et al, (2009) presented a case of complicated
iatrogenic low recto-vaginal fistula treated by interposition of
buccal mucosa and opposition of PRP (platelet rich plasma).
Similarly Gottgens et al, (2015) tried PRP injection into fistula
tract after mucosal advancement flap in 10 patients with
Crohn’s disease-related high perianal fistulas. They found that
Healing of the fistula was 70 % (95 confidence interval, 33–89
%) at 1 year. One patient (10%) had a recurrence, and in two
(20 %) patients, the fistula was persistent after treatment. They
concluded that results of this procedure in crohn's disease
fistulae are moderate with success rate of 70% and further
studies are needed.
PRP in urogynecology and genital prolapse
Genital fistulae

Genital fistulae are treated by many modalities listed in a systematic review of
Bodner-Adler et al, (2017) where conservative and surgical treatments were
assessed. They found that small fistulae could be treated conservatively with
different therapies including PRP with success rate ranged between 67%-100%.
PRP is tried in treatment of vesicovaginal fistula fistulae as a novel minimally
invasive approach for closure of genital fistulae.
Shirvan et al, (2013) in 12 patients tried the injection of platelet rich plasma
around the fistula into the tissue and platelet rich fibrin glue was interpositioned in
the tract. They followed cases for 6-months and found that 11 patients become
clinically cured, and transvaginal physical examination and cystography were
normal. They concluded that Autologous platelet rich plasma injection and
platelet rich fibrin glue interposition offer a safe, effective and novel minimally
invasive approach for the treatment of vesicovaginal fistula which obviate the need
for open surgery.
Genital fistulae

10 studies described non-surgical treatment strategies as sole
treatment option. These included transvaginal injection of fibrin
sealant in 1 case, Yag Laser welding in 8 patients, cystoscopic
electrocoagulation/fulguration/catheter method in 11 patients,
endovaginal application of cyanoacrylic glue in 3 cases, platelet
rich plasma/rich fibrin glue application in 6 women, curettage of
fistula tract in 3 cases and ball technique with rubber/metal ball in
18 females. Success ranged between 67%-100% and the majority
consisted of small VVF (<1 cm)

• Various types of vaginal implants, absorbable and non-
absorbable, that have been introduced in pelvic floor
reconstructive surgeries have numerous serious adverse
effects.
• Platelet rich fibrin (PRF) is a mixture of platelets,
leukocytes, cytokines, and circulating stem cells which is
optimal for stimulation of fibroblast migration and
proliferation. This mixture causes rapid remodeling and
connective tissue growth in vaginal surgery.
Genital prolapse

Gorlero et al, 2012 conducted a prospective observational study
on ten consecutive women requiring surgery for prolapse
recurrence (stage II or higher).
They operated cases plus injection of PRF.
They found that the success rate was 80% with complete symptom
relief. Sexual activity increased by 20% without dyspareunia.
They concluded that the use of PRF at site-specific prolapse repair
is associated with a good functional outcome. On the same hand,
Medel et al, (2015) found that attachment of fibroblast to vaginal
meshes was significantly increased after coating meshes with PRP
in-vitro.
Genital prolapse

Recently Chrysanthopoulou et al, (2017) in their study
summarized the existing evidence-animal
experimental and clinical studies- that address the
potential role of PRP in treating genital prolapse.
They concluded that PRP restore the anatomy and
function of pelvic ligaments but up till now there is no
evidence to support or oppose PRP use in women
suffering from genital prolapse.
Genital prolapse

On the other hand, another study was conducted to evaluate
whether autologous platelet gel application during anterior
colporrhaphy increases collagen content of the pubocervical
fascia and creates more durable repair.
They applied autologous platelet gel to the surgical site during
anterior colporrhaphy in 9 patients.
Biopsy specimens from the anterior vaginal wall at surgery and
3 months postoperatively were collected.
They found no significant increase occurred in collagen
content at 3 months after operation and they concluded that
autologous platelet gel didn't increase collagen or durability
of the repair.
Genital prolapse

Nikolopoulos et al, (2016) summarized
studies advocating the use of PRP in urinary
incontinence resulting from damage to the
pubourethral ligament. They found that PRP
helps in regulating tissue reconstruction and
restoration of pubourethral ligament strength;
but studies were not giving sufficient evidence
to validate its use.
Urinary incontinence

Surgical outcomes
Obstetrics
√
√
√

PRP in reproductive medicine
premature ovarian failure
Premature ovarian failure is a loss of normal function of the
ovaries before age 40 with loss of fertility.
A team of Harvard University researchers changed this fact
when they injected mice's ovary with growth factors and
appeared to develop mature eggs from ovarian stem cells.
They stated that introduction of isolated growth factor-bearing
platelets directly into the ovaries might trigger a resurgence in
oocyte production.

The possibility of ovarian rejuvenation
Autologous Platelet-Rich Plasma (PRP) Infusions and
Biomarkers of Ovarian Rejuvenation and Aging Mitigation

PRP therapy is recommended in women with premature ovarian failure
(POF), infertile women more than 35 years of age and women with low
ovarian reserve. Treatment with PRP is named ovarian rejuvenation where
PRP is injected into the ovary by ultrasound guidance like ovum retrieval in
IVF. This modality of treatment is still under trials. Pantos et al, (2016) in the
ESHRE annual conference held in 2016 at Helsinki, Finland introduced this
modality (Ovarian rejuvenation). They injected 8 peri-menopausal/POF
women with poor ovarian reserve. They found successful ovarian
rejuvenation 1-3 months after PRP treatment. All cases undergone natural
IVF cycles with resulting follicle of 15.20±2.05 mm in diameter and the
resulting oocytes were inseminated by ICSI and all resulted embryos were
cryopreserved.
premature ovarian failure

32nd Annual Meeting of ESHRE, Helsinki, Finland,
3 July – 6 July, 2016.

• The endometrium is an important factor involved in
achieving optimal outcomes after assisted reproductive
treatment. Endometrial growth following inadequate
ovarian stimulation may be neglected leading to poor
results of IVF/ICSI cycles. Different strategies been
suggested to improve endometrial thickness especially in
resistant cases. PRP is one of novel therapies tried in
those patients.
Refractory Endometrium

Colombo et al, (2017) included 8 patients to undergo PRP
treatment. The inclusion criteria were women with more
than 3 cancelled cryo-transfers due to poor endometrial
growth< 6 mm, women with negative hysteroscopic
screening for endometrial pathology, and women with
negative bacteriologic screening. After application of PRP,
the endometrial thickness was satisfactory in 7 cases. Of
these, beta-HCG was positive in 6 women. They concluded
that the multiple implantation failures were caused by
inefficient expression of adhesion molecules, which can
hypothetically be more represented after PRP application.

Zadehmodarres et al, (2017) in their pilot study include 10
patients who had a history of cancelled cycles due to
inadequate endometrial growth (less than 7 mm). They
found that endometrial thickness increased at 48 hours after
the first PRP and reached more than 7 mm after the second
PRP in all patients. Embryo transfer was then carried out for
all of them. Five patients were pregnant (50%) and in four
of them the pregnancy progressed normally. They
concluded that PRP was effective for endometrial growth in
patients with thin endometrium.(33)

• Several endometrial tissue remodeling studies have also
been performed on the proliferation, motility,
invasiveness and gel contractility of cultured human
endometrial stromal cells
• [Matsumoto, Nasu, Nishida, Ito, Bing, Miyakawa.
Regulation of proliferation, motility, and contractility of
human endometrial stromal cells by platelet-derived
growth factor. J. Clin. Endocrinol. Metab., 2005, 90(6),
3560-3567]. This is just a small sample of related data.

• Jang et al, (2017) in animal model tried to investigate the
role of PRP in regeneration of endometrium after ethanol
induced damage. They found that intrauterine
administration of autologous PRP stimulated and
accelerated regeneration of the endometrium and also
decreased fibrosis in a murine model of damaged
endometrium.
PRP in refractory endometrium

• Repeated implantation failure (RIF) is defined as failure to
conceive following several embryo transfers in in vitro
fertilization (IVF) cycles.
• Numerous factors are involved in process of implantation
including embryo quality, endometrial receptivity and
immunological factors.
• Several measures were suggested for RIF management but
there is little consensus on the most effective one. These
measures include blastocyst transfer, assisted hatching,
hysteroscopy, endometrial scratching, and immune therapy.
• Recently, intrauterine infusion of platelet-rich plasma (PRP) is
described to promote endometrial growth and receptivity.
Repeated implantation failure

• Nazari et al, (2016) enrolled 20 participants with RIF
history into their study to evaluate the effectiveness of
platelet-rich plasma in improvement of pregnancy rate in
RIF patients. The inclusion criteria were below 40 years
and their body mass index (BMI) below 30 kg/m2. They
found that 18/20 (90%) of participants got pregnant.
Sixteen clinical pregnancies were recorded and their
pregnancies are ongoing. They concluded that PRP is
effective in improvement of pregnancy outcome in RIF
patients.
Repeated implantation failure

Surgical outcomes
Obstetrics
√
√
√
√

PRP in Aesthetic gynecology
Breast reconstruction
• In this field of aesthetics and plastic surgery, many
studies were introduced but all studies were pilot studies,
small size sample or animal models. PRP plus adipose
tissue are given for breast reconstruction.

• Gentile et al, (2013) enrolled 100 patients aged between 19 and
60 years affected by breast soft-tissue defects. They divided
patients into 2 groups with equal allocation; the study group
was treated with fat grafting + PRP. The control group was
treated with fat grafting injection only.
• They found that patients treated with PRP added to the
autologous fat grafts showed a 69% maintenance of the
contour restoring and of 3-dimensional volume after 1 year,
whereas the patients of the control group treated with
centrifuged fat grafting showed a 39% maintenance.
• They concluded that PRP mixed with fat grafting leads to an
improvement in maintaining breast volume in patients affected
by breast soft-tissue defects. Similar results were obtained by
Salgarello et al, (2011).
Breast reconstruction

• Medical professionals know that platelets release around
35 growth factors that promote tissue regrowth, healing,
and regeneration. This fact was utilized by aesthetic
gynecologists in many aspects including vaginal
rejuvenation and O-shot therapy.
Female sexual dysfunction

• PRP use in sexual dysfunction is considered a
revolutionary new non-surgical office treatment that helps
improve both urinary incontinence and sexual
dysfunction through using woman's own growth factors.
The PRP is injected into specific areas of the vagina with
the aid of local anesthetic cream.
• This modality of treatment is called "o-shot". PRP
immediately activate tissue regeneration and the
enhancement in sexual response is dramatic. The desired
response includes improved arousal, stronger orgasm,
decreased dyspareunia, and increased natural lubrication.
PRP in female sexual dysfunction
O-Shot therapy

• Runels et al, (2014) enrolled 11 females presenting with
dyspareunia in their study. They injected PRP into clitoris
and vagina. They found that intravaginal and intraclitoral
PRP injections could be an effective method to treat
certain types of female sexual dysfunction, especially in
the areas of desire, arousal, lubrication and orgasm.

• Aesthetic practitioners use PRP in regeneration of vaginal
mucosa, muscles and skin. After PRP injection, vaginal
vascularity is increased with subsequent dramatic
increase in sensitivity.
• In addition, the skin becomes thicker and firmer, making
vagina looks much more youthful. More over ligaments
and muscles supporting urethera, become more stronger
alleviating urinary incontinence.
Vaginal rejuvination

• Kim et al, (2017) reported the use of PRP in one case for
vaginal rejuvenation. They concluded that application of
autologous lipofilling mixed with PRP in vaginal atrophy
produced relief of symptoms, contour restoration. The
rejuvenated appearance of external genitalia provided
pleasing cosmetic outcome to the patient.
PRP in vaginl rejuvenation

PRP in Obstetrics
• Premature rupture of membranes (PROM) occurs due to
damage and tears in the fetal membrane leading to congenital
infections and poor neonatal outcomes. PRP was tried in-vitro
model to evaluate the ability of platelet-rich plasma (PRP) in
sealing the iatrogenic fetal membrane defect. This was done on
single and double layers amnion models.
• The PRP plug was stable and attached firmly to amnion tear.
Authors concluded that there is experimental evidence that a
PRP plug persists for nearly 2 months in an amniotic fluid
environment. It also provides waterproof sealing of iatrogenic
defects in amnion and chorion. Moreover PRP stimulates cell
growth and proliferation and may thereby enhance a
membrane healing response.

Minia University
Sohag University
Assuit University
Tanta University
Clinicaltrial.gov

Platelet rich plasma is an innovative therapeutic modality
being cheap, simple, easily commenced, safe and effective.
It was tried in many fields of medicine and proved effective.
In gynecology studies are few, pilot or case series or case
reports. Large randomized controlled studies are required
for approval of the efficacy and safety of Platelet rich
plasma in gynecologic disorders.
Conclusions

Uses of prp in different gynecological disorders

Uses of prp in different gynecological disorders

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