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MODERN CONCEPTS OF TREATMENT OF ENDOMETRITIS WITH
CLINICAL APPLICATION OF PLATELET-RICH PLASMA IN THE
FEMALE REPRODUCTIVE SYSTEM
Nazarova Zebiniso Yusufjonovna
Bukhara State Medical Institute named after Abu Ali ibn Sino.
Bukhara, Uzbekistan. e-mail: nazarova.zebiniso@bsmi.uz
Annotation:
Platelet-rich plasma is an autologous plasma containing platelets
prepared from fresh whole blood drawn from a peripheral vein. Through processing,
it can be prepared to contain supraphysiologic levels of platelets at three to five times
greater than the level of normal plasma. PRP has been explored both in vivo and ex
vivo in the human endometrium model in its ability to harness the intrinsic
regenerative capacity of the endometrium. Intrauterine autologous PRP infusions
have been shown to increase endometrial thickness and reduce the rate of intrauterine
adhesions. In the setting of recurrent implantation failure, intrauterine infusion of PRP
has been shown to increase clinical pregnancy rate. PRP also appears to hold a
potential role in select patients with premature ovarian insufficiency, poor ovarian
responders and in improving outcomes following frozen–thawed transplantation of
autologous ovarian tissue. Further studies are required to explore the potential role of
PRP in reproductive medicine further, to help standardise PRP protocols and evaluate
which routes of administration are most effective.
Keywords
: gynaecology; platelet-rich plasma; infertility; endometrium; uterus
СОВРЕМЕННЫЕ КОНЦЕПЦИИ ЛЕЧЕНИЯ ЭНДОМЕТРИТА С
КЛИНИЧЕСКИМ ПРИМЕНЕНИЕМ БОГАТОЙ ТРОМБОЦИТАМИ
ПЛАЗМЫ В ЖЕНСКОЙ РЕПРОДУКТИВНОЙ СИСТЕМЕ
Назарова Зебинисо Юсуфжоновна
Бухарский государственный медицинский институт
имени Абу Али ибн Сино. Бухара, Узбекистан.
электронная почта: nazarova.zebiniso@bsmi.uz
Аннотация:
Богатая тромбоцитами плазма – это аутологичная плазма,
содержащая тромбоциты, полученная из свежей цельной крови, взятой из
периферической вены. Благодаря обработке ее можно приготовить так, чтобы
она содержала супрафизиологические уровни тромбоцитов, в три-пять раз
превышающие уровень нормальной плазмы. PRP исследовалась как in vivo, так
и ex vivo на модели эндометрия человека в отношении ее способности
использовать внутреннюю регенеративную способность эндометрия. Было
показано, что внутриматочные инфузии аутологичной PRP увеличивают
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толщину эндометрия и снижают частоту внутриматочных спаек. Было
показано, что в случае рецидивирующей неудачи имплантации внутриматочная
инфузия PRP увеличивает частоту клинической беременности. PRP также, по-
видимому, играет потенциальную роль у некоторых пациенток с
преждевременной недостаточностью яичников, плохим ответом яичников и в
улучшении результатов после замороженно-размороженной трансплантации
аутологичной ткани яичника. Необходимы дальнейшие исследования для
дальнейшего изучения потенциальной роли PRP в репродуктивной медицине,
чтобы помочь стандартизировать протоколы PRP и оценить, какие пути
введения наиболее эффективны.
Ключевые слова:
гинекология; богатая тромбоцитами плазма; бесплодие;
эндометрий; матка
AYOLLAR JINSIY TIZIMIDA TROMBOTSITLARGA BOY PLAZMANI
KLINIK QO‘LLASH ORQALI ENDOMETRITNI DAVOLASHNING
ZAMONAVIY KONTSEPTSIYALARI
Nazarova Zebiniso Yusufjonovna
Abu Ali ibn Sino nomidagi Buxoro davlat tibbiyot instituti. Buxoro,
Annotasiya:
Trombotsitlarga boy plazma - periferik tomirdan olingan yangi
qondan tayyorlangan trombotsitlarni o'z ichiga olgan otologik plazma. Qayta ishlash
orqali u trombotsitlarning suprafiziologik darajasini normal plazma darajasidan 3-5
baravar yuqori bo'lishiga tayyorlanishi mumkin. PRP inson endometrium modelida
ham in vivo, ham ex vivo o'rganilgan, uning endometriumning ichki regenerativ
qobiliyatidan foydalanish qobiliyati. Intrauterin otolog PRP infuziyalari endometrium
qalinligini oshirishi va intrauterin yopishish tezligini kamaytirishi ko'rsatilgan.
Takroriy implantatsiya etishmovchiligi sharoitida PRPning intrauterin infuzioni
klinik
homiladorlik
darajasini
oshirishi
ko'rsatilgan.
PRP,
shuningdek,
tuxumdonlarning muddatidan oldin etishmovchiligi bo'lgan tanlangan bemorlarda,
tuxumdonlarning yomon javob berishida va tuxumdonning avtonom to'qimalarining
muzlatilgan-eritilgan transplantatsiyasidan keyingi natijalarni yaxshilashda potentsial
rol o'ynaydi. PRP ning reproduktiv tibbiyotdagi potentsial rolini o'rganish, PRP
protokollarini standartlashtirish va qaysi yuborish yo'llari eng samarali ekanligini
baholash uchun qo'shimcha tadqiqotlar talab etiladi.
Kalit so‘zlar:
ginekologiya; trombotsitlarga boy plazma; bepushtlik;
endometrium; bachadon
The use of cell-based therapies, such as platelet-rich plasma (PRP), has gained
considerable momentum over the last decade due to their ability to promote tissue
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regeneration through cell differentiation and trophic activities. The first clinical
application of PRP was as a transfusion product to treat thrombocytopenia. It has since
been used across numerous medical fields, including maxillofacial and plastic
surgery, orthopaedic surgery, dermatology, urology and more recently gynaecology
.This review aims to summarise the use of PRP within the reproductive setting by
conducting an evidence-based evaluation of its preparation, classification systems,
mechanism of action and clinical applications. We aim to explore the potential
benefits of PRP on endometrial receptivity and regeneration, embryo implantation
and ovarian function.PRP is an autologous plasma containing platelets prepared from
fresh whole blood drawn from a peripheral vein. Through processing, it can be
prepared to contain supraphysiological levels of platelets at three to five times greater
than the level of normal plasma. Platelets are produced by megakaryocyte cells within
the bone marrow. They are anucleate and have the smallest density amongst all blood
cells with a diameter of 2 μL. Their physiologic count ranges from 150,000 to 400,000
platelets per μL. Given their small density, centrifugation methods result in platelets
settling at the top of an aggregate, which allows for efficient extraction and
subsequent clinical use.PRP contains alpha granules storing cytokines and growth
factors, which are key to tissue regeneration. Growth factors within the alpha granules
include vascular endothelial growth factor (VEGF), transforming growth factor
(TGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF),
insulin-like growth factor-1 (IGF-1), connective tissue growth factor (CTGF) and
fibroblast growth factor (FGF). These growth factors regulate cellular migration,
differentiation and proliferation through autocrine and paracrine effects. The alpha
granules containing growth factors are released within ten minutes of platelet
activation at the site of injury or inflammation, resulting in a net flow of neutrophils
and macrophages, which leads to angiogenesis and re-epithelialisation. Specifically
within the human endometrial model, the release of PDGF has proven to be key to
endometrial progenitor cell activity. PDGF isoforms have been demonstrated to
significantly improve endometrial stromal cell proliferation and contractility.The
outer membrane of platelets consists of a phospholipid bilayer which provides the
structural foundation of the platelet cell membrane. Phospholipids within the serum
have been demonstrated to negatively correlate with the level of phospholipid within
the follicular fluid within the ovarian follicles during controlled ovarian stimulation
cycles in patients undergoing IVF. This has been hypothesised to result from the
increased consumption of platelets secondary to increased membranogenesis taking
place during follicular growth. Therefore, an increased serum level of platelets
through the addition of PRP, resulting in an increased level of serum phospholipid,
may benefit follicular growth and thus improved oocyte during IVF cycles. To add to
this, Fayezi and colleagues discovered that the amounts of phospholipid and the
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phospholipid/apoA-I ratio in follicular fluid were associated negatively with the
percentage of fertilised oocytes.
Types of PRP
The growth factors secreted by platelets which are available to tissues have been
shown to be directly proportional to the platelet concentration. Bone and enhanced
soft-tissue healing have been proven to occur at platelet concentrations of 1,000,000
plate-lets/μL within a 5mL volume of plasma; thus, this is often used as a working
definition of therapeutic PRP. In the presence of varying concentrations of platelets
within a platelet gel, human endothelial cells have displayed induced proliferation,
motility and enhanced invasiveness in the pattern of a bell-shaped distribution,
whereby higher concentrations have resulted in a reversal of the processes. The
optimal concentration for platelet stimulation and proliferation was reported to be
1.25 × 106 and for angiogenesis, 1.5 × 106 platelets/mL.
Endometritis
Chronic endometritis is defined as persistent inflammation of the endometrial
mucosa caused by bacterial pathogens. Diagnosis of chronic endometritis is made
through sampling of the endometrium at hysteroscopy and the presence of plasma
cells within the endometrial stroma on histological analysis. The level of
proinflammatory cytokines interleukin-6, interleukin-1β and tumour necrosis factor α
are increased in women with chronic endometritis, which may affect cell migration
and proliferation. It has been associated with repeat implantation failure and recurrent
miscarriage. Current treatment for chronic endometritis rests largely on oral
antibiotics. However, although antibiotic treatment has been shown to improve the
implantation and clinical pregnancy rates, those with ongoing chronic endometritis
may continue to experience fertility issues compared to women successfully treated.
Autologous PRP represents a novel treatment approach for chronic endometritis. One
recent case study demonstrated a successful live birth following intrauterine infusion
of PRP in a patient with a history of chronic endometritis and six failed embryo
transfers. Microbiological and scanning electron microscopy analysis during a
subsequent menstrual cycle following an intrauterine PRP infusion revealed no
evidence of chronic endometritis. In the bovine model in vitro, PRP has been shown
to downregulate the expression of proinflammatory cytokines IL-1β, IL-8 and iNOS.
Additionally, PRP has been shown to upregulate the expression of ER-α, ER-β and
PR genes, which are vital for pregnancy. Furthermore, in the equine model in vivo,
intrauterine infusion of PRP displayed a reduction in the intrauterine inflammatory
response as measured by the percentage of neutrophils in uterine cytology and the
nitric oxide concentration within the uterine fluid. In clinical settings such as
endometritis where endometrial regeneration is impaired, PRP has been shown to
increase the expression of matrix metalloproteinases (MMP) MMP3, MMP7 and
MMP26 within the endometrial stromal fibroblasts and mesenchymal stem cells.
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MMPs have been shown to be vital for successful wound healing—an important step
in recovery from endometritis. As provisional, albeit limited, outcomes from animal
studies appear promising, there is a further need for well-designed studies in humans.
Refractory Endometrium
In each menstrual cycle, there exists a period of four to five ‘opportune’ days for
the human embryo to implant when the endometrium remains receptive. The
endometrial microenvironment determines endometrial receptivity. This is governed
by changes to the uterine luminal and glandular cells, decidualisation of the
endometrial stroma and increased leukocyte activity. Sonographic markers, such as
endometrial thickness and uterine artery blood flow, have proven to have a high
negative predictive value and a low positive predictive value for a receptive
endometrium. Nevertheless, studies have demonstrated an endometrial thickness of 7
mm and above to be optimal for implantation and to result in improved clinical
pregnancy rates. An endometrial thickness <7 mm, which is unresponsive to
hormonal therapy, has been defined as a refractory endometrium and is associated
with suboptimal fertility rates. A severe deficiency in angiogenic-related markers has
been demonstrated in patients with a refractory endometrium, specifically leukemia
inhibitory factor, vascular endothelial growth factor (VEGF) and β 3 integrin.Thus,
given the proangiogenic potential of autologous PRP, its application in the setting of
subfertility secondary to refractory endometrium presents an exciting opportunity for
patients who are unresponsive to conventional treatment methods.
RESULT
Intrauterine infusion of PRP represents a novel strategy for the treatment of the
endometrium in its ability to promote biological processes for endometrial
regeneration. Data on the benefit of PRP within the reproductive setting still remain
scarce. However, the theoretical benefits and positive preliminary findings suggest
great potential in other indications within reproductive medicine . PRP offers an
exciting opportunity to enhance ovarian reserve in the context of POI, poor ovarian
response and potentially in the context of ovarian cortex transplantation. PRP remains
a relatively low-cost therapeutic intervention given that it can be prepared at the
patient’s bedside with minimal equipment and can be administered in the office
setting quickly and effectively. The use of autologous blood to produce PRP has
eliminated the risk of immunological reactions and presents a widespread opportunity
for its use in the field of gynaecology. However, differences in PRP preparation can
produce a heterogenous injectate, which may vary in quality, purity and quantity. One
such example is the variation of centrifugation speed and duration where higher
speeds can result in a greater concentration of platelets but may also result in more
contaminants or disruption in the platelet integrity. Future studies should define the
cellular content of PRP, including the white and red cell counts, the concentration
factor and the platelet yield—a valuable step in producing a robust product for clinical
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application. Moreover, further studies need to evaluate the optimal methods and
routes of administration. Despite the clear potential of the role of PRP in reproductive
medicine, well-designed, randomised, prospective studies are essential before usage
can be recommended. One particularly valuable area of focus is the effect of PRP in
the activation and growth of ovarian follicles in addition to the potential for reversal
of ovarian ageing.
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