**4.1 Ovulation induction agents**

First-line treatment for ovulation induction in the treatment of infertility in PCOS are oral agents, with letrozole being superior to clomiphene citrate (CC) in terms of endometrial thickness and markers of endometrial receptivity [7, 91, 92]. Gonadotropins are the second line treatment and it seems that they have a less deleterious impact on endometrium [93]. However, no data today support the ovulation induction in infertile ovulatory PCOS for the modification of endometrial receptivity.

Several studies evaluated the different impact of ovarian stimulation with letrozole versus clomiphene citrate in patients with PCOS. Thus, Wallace et al. published in 2011 a randomized controlled study which reported that letrozole positively influenced a number of markers of endometrial receptivity like mRNA expression of leukemia inhibitory factor, dickkhopf homolog 1, fibroblast growth factor 22 compared with CC [94]. Another randomized controlled study which included 160 patients diagnosed with PCOS found that indices of endometrial receptivity like the volume, vascularization index, flow index and vascularization flow index of endometrium on the day of hCG administration and 7–9 days after ovulation were significantly increased in letrozole group compared with CC [95]. Moreover, the biochemical pregnancy rate, clinical pregnancy rate and ongoing pregnancy rate in letrozole group were significantly higher compared with CC group [95]. The same authors evaluated the indices of endometrial receptivity in treated PCOS patients (Letrozole or clomiphene citrate) and non-treated [96]. They noticed that, although the successful ovulation rate did not differ between the letrozole group and CC group, endometrial thickness, endometrial volume, vascularization index, flow index, vascularization flow index, integrin αvβ3 and VEGF concentrations in uterine fluid were significantly higher in the window of implantation in the letrozole group compared with the CC group and natural cycle group [96]. Moreover, the clinical pregnancy and ongoing pregnancy rates of the letrozole group were significantly higher than in the CC group [96]. The markers of endometrial receptivity analyzed were significantly higher in pregnant patients [96]. The endometrial flow index during the implantation window had the highest predictive value for pregnancy. The integrin αvβ3 in uterine fluid had better predictive value than VEGF [96].

In an experimental study on female rats it was found that the expression of integrin αvβ3 in the clomiphene citrate group was lower than in the letrozole and saline solution groups [97]. The expression of HOXA10 was statistically significantly higher in the saline solution group than in the letrozole group, and the letrozole group showed a statistically significantly higher expression of HOXA10 compared with the clomiphene citrate group. The authors concluded that, in rats, letrozole affects the expression of HOXA10 in uterine epithelium but has no effect on the expression of integrin αvβ3, which suggests that clomiphene suppresses endometrial receptivity more than letrozole.

## **4.2 Antiandrogens**

Antiandrogens as flutamide, finasteride and spironolactone are used in clinical practice to improve the signs of clinical hyperandrogenism like hirsutism, acne, alopecia. Animal studies demonstrated the ability of antiandrogens to improve endometrial function [98, 99]. However, their use in patients seeking infertility treatment is prohibited by their teratogenic effects, being generally recommended to be administrated only in association with oral contraception [100]. Another way to improve hyperandrogenism is by administration of combined oral contraceptives which decrease ovarian androgen production and decrease androgen bioavailability through stimulation of sex hormone binding globulin production. Indeed, oral contraceptives, administrated in a successive or unsuccessive manner before in vitro fertilization, were showed to increase the implantation and pregnancy rate and reduce the risk of pregnancy complications along with significant decrease in circulating androgens [101]. However, in a randomized controlled trial ovulation rate and live birth rate were superior in PCOS patients receiving life style modification with or without oral contraceptive in comparison with oral contraceptive alone [102].

#### **4.3 Freeze all strategy**

Elective frozen embryo transfer after a freeze-all strategy was suggested for infertile PCOS patients undergoing IVF [103]. This approach could be particularly effective in PCOS due to exposure of the endometrium to high estrogen levels during controlled ovarian stimulation. Thus, transfer of the embryo in a subsequent cycle may avoid failure of implantation due to inadequate endometrium receptivity. This strategy was showed of particular benefit in PCOS patients and only in case of more than 16 oocytes or estradiol higher than 3000 pg./ml, resulting in higher live birth rate [104]. Regarding the preparation of endometrium, it seems that the pregnancy rate is higher in natural cycles over the hormone replacement cycles in women performing frozen embryo transfer [105]. However, specific data for PCOS women are lacking.

In women with PCOS, no difference in live birth/ongoing pregnancy and clinical pregnancy rates was detected between FET cycles stimulated with hMG and cycles artificially prepared with E2 valerate [106–108].

#### **4.4 Gut microbiota and endometrial receptivity**

There is accumulating evidence that gut microbiota might play a role in PCOS pathogenesis [109, 110]. Thus, it was showed that gut microbiota of PCOS patients is different from controls [111] and that variate profiles of gut microbiota are associated with features of PCOS such as hyperandrogenism [112], hyperinsulinemia and insulin resistance [113] and obesity [114]. In experimental studies transplantation of feces from PCOS women leads to development of PCOS features in mice [109] and oral administration of variate bacteria was associated with improvement of PCOS manifestation [110]. Thus, Qi X et al. [109] showed that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS and that transplantation of fecal microbiota from women with PCOS or B. vulgatuscolonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility [109]. It was also showed that IL-22 improved the PCOS phenotype [109]. Guo Y et al. [110] showed that PCOS rats displayed different composition of gut microbiota that in the controls. Lactobacillus, Ruminococcus and Clostridium were lower while Prevotella was higher in PCOS rats when compared with control rats. After treating PCOS rats with Lactobacillus and fecal microbiota transplantation from healthy rats estrous cycles were improved with decreasing androgen biosynthesis [110].

However, it is possible that the relationship between gut microbiota and PCOS to be bidirectional since in androgen-induced PCOS animal models the disturbances of gut microbiota was reported [115, 116]. In turn, DHEA-shaped gut microbiota transplanted to pseudo germ-free rats recipients trigged disturbances in

#### *Endometrial Receptivity in Patients with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.98624*

reproductive hormone [115]. Another study showed that both androgens and high fat diet could shift the overall gut microbial composition, being associated with the development and pathology of PCOS by shaping gut microbial communities [117]. Although direct evidence of a connection between gut microbiota and endometrial receptivity was not reported yet, we can hypothesize a connection between these two due to the recognized involvement of insulin resistance, hyperandrogenemia and obesity in endometrial receptivity which, in turn, can be shaped by intestinal bacterial community.

Regarding the mechanisms connecting gut microbiota and PCOS, Tremellen and Pearce suggest that dysbiosis of the gut microbiota brought about by a high fat-sugar diet in PCOS patients leads to an increase in intestinal permeability. Lipopolysaccharide produced by Gram-negative bacteria traverse the gut wall to enter the circulation, leading to a chronic state of low-grade inflammation. Activation of the immune system interferes with insulin receptor, driving up insulin levels, which boost testosterone production in the ovary, leading to PCOS [118].

Another way by which gut microbiota might influence the endometrial receptivity is through its recently demonstrated close connection with genital tract microbiota [119–122]. The crosstalk between gut and vaginal microbiota is highlighted by studies showing that oral administration of probiotics or bacteria can influence immunity in the vagina [120]. Thus, oral administration of Lactobacillus johnsonii was showed to inhibit the expression of inflammatory molecules in the vagina and to alleviate Gardnerella vaginalis induced vaginosis [122]. Kutteh et al. [121] demonstrated that intestinal tract immunization by oral and rectal route is followed by the induction of specific antibodies in human female genital tract secretions [Kutteh 2001]. Kim et al. [120] showed that in ovarectomized female mice, the oral administration of anti-inflammatory *Lactobacillus plantarum* NK3 and Bifidobacterium longum NK49 from kimchi and human fecal lactic acid bacteria collection was associated with alleviation of Gardnerella vaginalis induced vaginosis, inhibition of NF-κB activation and TNF-α expression in the vagina and uterus, and decreased the Gardnerella vaginalis population in the vagina [120]. In turn, Gardnerella vaginalisinduced vaginosis increased colonic myeloperoxidase activity, TNF-α expression, and fecal Proteobacteria population. NK3 and/or NK49 treatments reduced TNF-α expression and NF-κB activation in the colon and restored Gardnerella vaginalis disrupted gut microbiota composition [120].

This interplay between gut and reproductive tract microbiota may be related with endometrium function since, recently, it was showed that pathological modification of the profile of the bacterial community of the endometrial fluid might play a role in poor reproductive outcome for in vitro fertilization patients [123]. Thus, the presence of a non-Lactobacillus-dominated microbiota in a receptive endometrium was associated with significant decreases in implantation, pregnancy, ongoing pregnancy, and live birth rates [123]. Haahr et al. [124] found a decreased pregnancy rate in patients with abnormal vaginal microbiota performing IVF [124]. These studies highlight the importance of reproductive tract microbiota in fertility, possibly by modulation of endometrial receptivity.

All these data offer future therapeutic strategies to counteract decreased endometrial receptivity in PCOS women by modulating gut or reproductive tract microbiota or by administration of interleukin 22 as suggested by Qi X et al. [109].

#### **4.5 Assessment of endometrial receptivity and therapeutical implications**

The evaluation of endometrial receptivity was historically done by endometrial histology. However, recent studies find little concordance with new transcriptomic methods of endometrial receptivity assessment [125]. Endometrial receptivity array (ERA) is a test that analyzes the gene expression of the endometrium using a panel of 238 genes that have been implicated in endometrial receptivity. The indication of this test in the clinical practice is to identify the window of implantation in patients with accelerated or delayed endometrial luteal phase development, therefore allowing the transfer of the embryo in the right moment for the embryonic-endometrial synchrony. However, data regarding the benefit of this test are limited [126]. Although in PCOS patients performing IVF ERA test has hypothetical indications, studies evaluating this aspect are lacking.

Another aspect that should be clarified further is the consistency of the ERA findings from cycle to cycle since the transfer of the embryo should be done in a non-biopsy cycle. This aspect was analyzed in seven women who performed the ERA test in separate endometrial samples obtained 29–40 months apart and found high similarity across the samples [127]. However, only five samples were from the luteal phase and only four were in the receptive phase, all the samples being normal. Therefore, the possibility to extrapolate these findings to patients with endometrium receptivity abnormalities or dyssynchrony is unknown.

The ERA test was studied in several categories of infertile patients. Tan et al. [128] found that among patients with a history of at least one euploid blastocyst implantation failure personalized frozen embryo transfer (FET) according to ERA test results was superior to standard FET in terms of implantation and ongoing pregnancy rate, although the difference was not statistically different [128]. Other studies showed a similar pregnancy rate between patients with receptive and non-receptive endometrium according to the ERA test when a personalized embryo transfer was performed in patients with recurrent implantation failure [129] or with a history of implantation failure [125]. On the other hand, Eisman et al. [130] found a similar pregnancy rate in women who had a prior failed embryo transfer and personalized frozen embryo transfer following ERA test compared with women without a prior failed embryo transfer [130]. However, the pregnancy rate was lower in patients with more than three failed embryo transfer despite personalized transfer [130].

A multicenter, open-label randomized controlled trial evaluated patients at their first appointment for IVF after exclusion of patients with recurrent miscarriage and implantation failure. They found that a personalized frozen embryo transfer guided by ERA test was superior in terms of cumulative pregnancy and live birth rate to standard frozen embryo transfers and fresh embryo transfers [131]. At the first embryo transfer cycle, although the pregnancy rate and implantation rates were significantly higher compared with the two groups without ERA guidance, the live birth rates were similar [131]. Basil et al. [132] performed a single center retrospective cohort study and found that using the ERA test in patients undergoing frozen embryo transfer, there is no benefit in terms of ongoing pregnancy rate in good prognosis patients [132].

Taken all together, these studies suggest that the ERA test might be beneficial in patients with implantation failure, although future studies are necessary to clarify this aspect. In patients at their first attempt of IVF personalized frozen embryo transfer guided by ERA test may increase the cumulative pregnancy and live birth rate, although without obvious benefits at the first transfer. Whether these results are also valid for PCOS patients remains to be established.

#### **5. Conclusion**

An increasing body of evidence suggests that endometrial receptivity in PCOS patients is decreased, being a significant contributor to infertility in these patients. However, specific strategies to overcome this barrier in infertile PCOS women should be created in order to improve fertility treatment outcome.

*Endometrial Receptivity in Patients with Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.98624*
