The flip side of the coin: is the endometrium ready for IVM-derived embryo implantation?

As basic research and clinical trials refocus prospects for human oocyte in vitro maturation (IVM), the role of the endometrium in this treatment strategy remains a missing piece of the puzzle.

It is without doubt that clinical IVM is poised to represent a milestone in contemporary ARTs. The success of the development and implementation of this technique is still ongoing but undisputed, and recent IVM outcome reports are comparable in safety and efficacy to conventional in vitro fertilization (IVF). While IVM is likely to be an ideal choice for certain indications, more research is needed. Based on the results mainly from women with PCOS, more than 4000 babies were born using ART and IVM. No increase in congenital disabilities or developmental delays due to IVM was reported in these babies. Several case reports had reported live births in women undergoing cancer treatment when IVM was performed with immature oocytes obtained ex vivo after oophorectomy [1]. The most appropriate candidates for IVM, as noted elsewhere in this issue of JARG, include (i) PCOS patients to eliminate ovarian hyperstimulation syndrome; (ii) cancer and premature ovarian insufficiency (POI) patients for fertility preservation; (iii) normo-ovulatory women for reduced cost, drug-related side effects, and psychological stress; (iv) over-responders and ovarian resistance to FSH; and (v) fertile young women to preserve their fertility to manage the “ticking clock” issue for social reasons.

The likelihood of inadequate endometrial preparation in the IVM cycle is a significant concern. Currently, there is limited data regarding the endometrial preparation for IVM-derived embryos in the literature. Although the clinical pregnancy rate and implantation rate were comparable in IVM and conventional IVF cycles, the miscarriage rate was significantly higher in the IVM group [2, 3]. The authors suggested that the difference between the IVM and IVF groups is related to PCOS rather than to the IVM procedure. Others have shown comparable perinatal outcomes, including major and minor malformations [4, 5]. A recent study compared embryonic developmental competence and clinical outcomes of oocytes matured in vivo (IVF oocytes) and those grown in vitro (IVM oocytes) from the same IVM/IVF cycles and analyzed the clinical efficiency of a melatonin-supplemented in vitro maturation system combined with a modified IVM/IVF protocol [6]. They concluded that the modified IVM/IVF protocol could be effectively applied to the treatment of some indicated patients, even though the developmental potential of IVM oocytes may not be as high as IVF oocytes.

The challenge with IVM is the lack of physiological periovulatory hormonal and endometrial changes of a natural cycle due to the recruitment of oocytes in an IVM cycle in the mid-follicular phase of the ovulatory cycle or the proliferative phase of an anovulatory cycle. Meanwhile, although the endometrium has begun to proliferate, it has not yet reached a mature preovulatory endometrium thickness; therefore, ultrasonographic data on conventional IVF, oocyte donation, optimal endometrial thickness from frozen-thawed embryo transfer cycles may not be usable during IVM. In all these techniques, the aim is to achieve synchronization between the receptive endometrium and embryo development. Studies are urgently needed to fill knowledge gaps on this subject.

Proliferation and secretory changes of the endometrium are influenced by the steroid hormones estradiol (E2) and progesterone (P4), and implantation depends on the quality of the embryo and the endometrium. Inadequate exposure of the endometrium to these hormones may lead to implantation failure or miscarriage. Moreover, the endometrium selectively discriminates between high-and low-quality embryos like a bio-sensor to guarantee successful implantation [7]. While there was no difference in the mean endometrial thickness on the day of immature oocyte collection (OIC) between pregnant and non-pregnant women [8], women with PCOS have a thin endometrium on the day of OIC, and the pregnancy rates were comparable to IVF [8–10]. To open the implantation window for the embryo obtained with IVM, the endometrium must reach a sufficient proliferation level before being under the influence of P4. The window of implantation (WOI) is a short specific time interval, corresponding to the mid-secretory phase in the endometrial cycle when the endometrium becomes receptive to the blastocyst. Within this timeframe, an emerging concept is that the proper molecular crosstalk between the endometrium and the blastocyst is of utmost relevance to ensure proper implantation [11]. WOI development is regulated by gland development and function, decidualization, immune cells, a wide variety of cytokines, growth factors, prostaglandins, enzymes, cell adhesion molecules, and ECM proteins and pinopodes (also known as uterodomes) [11, 12]. A series of genes have been linked to endometrial receptivity. Our group has recently found that endometrial epithelial FoxO1 expression is finely regulated by the implanting embryo and pregnancy hormones which makes this transcription factor an emerging marker of endometrial receptivity and thus improves the outcomes of ART in the clinic [13, 14]. So far, the only known unquestionable marker for uterine receptivity in the human, however, is implantation. Prospective studies comparing different protocols for optimal endometrial preparation in IVM cycles are still lacking.

The most appropriate candidates for IVM are PCOS patients. It is known that PCOS is associated with an increased risk of pregnancy-induced hypertension, preeclampsia, and premature delivery, which may be related to abnormal endometrial function and impaired implantation process. Thus, here are some critical questions that need to be answered. What happens in the endometrium of PCOS patients, regardless of their ovaries? What is the endometrium-related pathogenesis in women with PCOS? There is indeed an altered endometrial milieu. Well-validated endometrial markers for clinical practice predicting the clinical outcomes in women with PCOS are still lacking. In recent years, an increasing number of studies have revealed several endometrial biomarkers related to the PCOS phenotype, possibly explaining some of the unfavorable endometrium-related clinical manifestations. However, the PCOS population is quite heterogeneous, and it is difficult to separate the effects of factors such as obesity, hyperinsulinemia, and inflammation from the syndrome itself [15]. What about other patient populations who might benefit from IVM? Here, fertility preservation advances have rekindled interest.

Do cancer therapies damage the uterus and compromise fertility? Fertility preservation patients are also appropriate candidates for IVM. To date, most research related to fertility preservation has focused on protecting ovarian function [16]. However, the endometrium is likely injured by chemotherapy and radiation as well. Cancer therapies can cause longstanding effects on the uterus and ovaries that can impair hormonal regulation, causing sub-infertility or infertility. We should be looking beyond the ovary for oncofertility care in women, with “uterine injury” as a potential target for fertility-preserving therapies [17]. Current data raise the possibility that anti-cancer agents may inflict permanent damage to the uterus and compromise its ability to establish and support pregnancy [18]. There is already evidence that the prepubertal uterus is damaged by radiotherapy; this can affect pregnancy success in adulthood. On the other hand, there is no comprehensive literature yet to show whether and to what extent the uterus of adolescents or adults treated with radiotherapy or chemotherapy is damaged. We need a better understanding of uterine damage caused by chemotherapy and radiotherapy to approve an “all-inclusive approach to fertility preservation” in pre-and post-pubertal cancer survivors. We also need a research agenda related to this issue.

Taken together, IVM is a promising option for some women with PCOS and in need of fertility preservation. Improving the oocyte/embryo quality achieved with IVM is important. For a successful IVM outcome, more knowledge is needed about endometrial quality, which is the other side of the coin. Imagine Guns N’ Roses playing, and the IVM-derived embryo is “knockin’ on heaven’s door.” Do we know whether the soil is fertile?