**1. Introduction**

The overall objective of this review was to determine if platelet-rich plasma (PRP) infusions are viable alternatives to current treatments for thin endometrial lining, and to distinguish if PRP infusions increase endometrial thickness and implantation in patients that underwent treatment in eight different case studies.

Platelet-rich plasma is prepared from autologous whole blood collected from a patient's peripheral vein, mixed with an acid citrate dextrose solution A (ACD-A) anticoagulant, and processed to separate platelets from remaining blood components [1]. Platelet-rich plasma is recognized as plasma from autologous blood with 4–5 times the concentration of normal platelet levels; these high concentrations of PRP contain cytokines and growth factors including: vascular endothelial growth factor (VEGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) [2, 3]. Because of the expression of several regenerative growth factors, PRP is being used in several fields of medicine to promote wound regeneration including: arthritis, nerve injury, tendinitis, bone regeneration, cardiac muscle repair, alopecia, and plastic and oral surgery recovery [4, 5]. When the body is injured, a natural healing process occurs that floods the wound site with activated platelets that instantly promote cell regeneration and proliferation. It is theorized that PRP may be used to promote the same growth and proliferation in endometrium that have previous suboptimal growth patterns. Similar research, such as endometrial scratching, has been studied to promote the generation of growth factors to increase implantation; however, the concentration of platelet levels within direct PRP infusion into the endometrium is vastly superior to the natural, localized endometrial healing process that occurs with the scratching method.

Other treatment strategies for thin endometrial lining have varied throughout recent years, but have been inclusive of extended use of exogenous estradiol, lowdose aspirin, vitamin E supplementation, and use of granulocyte colony stimulation factor (G-CSF), but not all have been proven effective [6–9]. The minimal endometrial thickness suggested for successful implantation at embryo transfer is 7 mm [10], however, there are those that argue endometrial lining is a poor indicator for pregnancy outcomes and therefore should not be heavily considered [11]. During typical HRT cycles, estradiol administration is regulated from day 2 or day 3 of an average 28 day cycle and continues until the endometrial lining reaches optimal thickness for transfer (typically >7 mm) at which time progesterone administration then occurs [12]. This model is utilized in IVF clinics globally; however, patients who fail to reach the recommended endometrial thickness often undergo canceled cycles in which they have wasted valuable time, medications, and expenses without receiving an embryo transfer.

Thin endometrial lining or suboptimal endometrial growth is a problem that affects up to 5% of the patients undergoing IVF treatment [13]. These patients often experience the emotionally and physically traumatizing effects of canceled cycles or repeated implantation failure (RIF). It is proven that growth factors expressed in the endometrium of women with RIF are less than those expressed in normal fertile women [14]. These growth factors can be stimulated by infusion of autologous PRP into the endometrium in conjunction with HRT prior to embryo transfer. However, many factors are involved in successful embryonic implantation, not limited to embryo quality, but also a synchrony between the embryo and the endometrium in addition to any immunological factors [15]. Without optimal endometrial growth, this synchrony becomes far less likely as the endometrium does not express the adequate genes nor growth factors involved in embryonic implantation [16, 17].

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added to estradiol dosages.

*Autologous Platelet-Rich Plasma Infusion to Improve Pregnancy Outcome in Suboptimal…*

Through multiple studies, PRP processing was performed similarly. On the 10th day of HRT, Chang and coworkers drew 15 ml of autologous blood into a tube with 5 ml of Acid Citrate A Anticoagulant (ACD-A) and centrifuged; separating red blood cells, a gel buffy coat, and cellular plasma. The plasma and buffy coat were then transferred to a second tube and centrifuged again, yielding 0.5–1 ml of PRP [18]. Both Zadehmodarres and Nazari and their colleagues drew 17.5 ml of blood on day 9 or 10 of HRT into 2.5 ml of ACD-A and similarly centrifuged twice to obtain 0.5 ml of PRP [19, 20]. Tandulwadkar et al. used 10 ml of autologous blood into an unspecified amount of ACD-A; which was centrifuged sequentially utilizing first a soft spin for 15 minutes, followed by a hard spin for 6 minutes, again yielding between 0.5 and 0.8 ml of PRP [21]. Eftekhar and others used an alternative approach, collecting PRP on the 13th day of HRT by drawing 8.5 ml of peripheral venous blood into a syringe containing 1.5 ml of ACD-A that was then centrifuged for 10 minutes; following first centrifugation, the buffy coat and plasma layer were then removed and centrifuged again, yielding 1.5 ml of PRP [22]. Meanwhile, Hounyoung et al. collected 18 ml of venous blood in a 30 ml syringe prepared with 2 CC of ACD-A and then centrifuged twice to obtain 0.7–1.0 ml of PRP [23]. Nazari and coworkers performed a follow-up study utilizing a double-blinded trial in which 30 patients underwent PRP infusion, prepared in the same manner as the initial pilot study [19], and 30 patients underwent placebo PRP infusions [24]. Chang et al. performed a secondary study as well, involving a larger cohort of patients compared against a control group, and performed PRP collection as previously reported [18, 25]. All studies transfused the PRP into the endometrium using an IUI catheter, and then repeated intravaginal ultrasound 48 hours later to measure endometrial growth; patients who did not reach the desired lining thickness (>7 mm deemed adequate in all studies) were then treated with a second round

In the past, IVF clinics allowed for natural cycle frozen embryo transfer in which they permitted endometrial lining to develop on its own, but it resulted in many timing issues with need for frequent monitoring and cancelation due to anovulation and poor development of the endometrium. Today, most clinics have moved fully to HRT protocols that allow for artificial stimulation of the endometrium that can be easily tracked utilizing blood serum and ultrasound assessment to time an embryo transfer concordant with a receptive endometrium. In humans, estrogen stimulates endometrial growth and induces progesterone receptors as it moves naturally through the menstrual cycle. After ovulation, the endometrium is exposed to progesterone which induces morphological and biochemical changes that alter the endometrium from the proliferative phase to the secretory phase [17]. In HRT cycles, estradiol administration (typically Estradiol Valerate) occurs until the lining has reached a thickness of greater than 7 mm, at which time progesterone is then administered for the number of days proportional to the embryo being transferred (i.e., a day 6 blastocyst will receive progesterone for 6 days) and then the embryo is transferred to a supposedly receptive endometrium [26, 27]. In these HRT cycles, patients receive estradiol during the follicular phase that inhibits gonadotropin secretion and prevents follicular development and ovulation. The start of the luteal phase can be exactly pinpointed, as it starts when progesterone is

*DOI: http://dx.doi.org/10.5772/intechopen.90651*

**2. PRP collection and infusion**

of PRP infusion [18–25].

**2.1 Hormone replacement therapy**

*Autologous Platelet-Rich Plasma Infusion to Improve Pregnancy Outcome in Suboptimal… DOI: http://dx.doi.org/10.5772/intechopen.90651*
