Enhancing Endometrial Receptivity Assessment Outcomes in Recurrent Implantation Failure: Intralipid Infusion and Acupuncture as Complementary Therapies.

The infertility clinic in Maharashtra, India, received a visit from an infertile couple. The couple, who are 35 years old and 36 years old, complained of primary infertility for the previous 7 years. The procedures, advantages, and disadvantages were thoroughly explained to them. Both people provided their informed consent. To determine the cause of infertility, both underwent extensive assessments. After analyzing the husband’s semen report, the count was 55 million/mL, the normal morphology was 5%, and the motility was 62%. According to the investigation, the report was normal. The female patient underwent an anti-Mullerian hormone (AMH) test; the report revealed a low ovarian reserve of 0.4 ng/mL. Endometrium assessment shows a low endometrium thickness of 6.2 mm. A hysteroscopy also identified minor intrauterine adhesions, which could affect implantation success. The female body mass index (BMI) was 21.5 kg/m 2 , while the male was 25.5S kg/m 2 . A medical examination indicated that both partners were within normal limits. The couple reportedly had no history of surgical interventions. The couple had no medical history. On day 2 of the menstrual cycle, the female patient was advised to get treatment with a gonadotropin-releasing hormone antagonist. 10,000 IU of human chorionic gonadotropin (hCG), which helps in egg maturation, was subcutaneously injected into the patient on day 14. After 36 hours of stimulation, oocyte retrieval was advised for the patient. Ten oocytes were extracted during the process: three at the germinal vesicle stage, three at the metaphase I (MI) stage, and four at the MII stage. After an hour of ovum pickup (OPU), ICSI was carried out on the same day with four MII and three MI oocytes. After 5 days of ICSI, fresh embryo transfer was carried out, resulting in implantation failure. For the second ovum retrieval cycle, the patient was again advised for the GnRH antagonist protocol; then, after 36 hours, OPU was scheduled; 11 oocytes were retrieved: three at the germinal vesicle stage, three at the metaphase I (MI) stage, and five at the MII stage. After an hour of OPU, ICSI was carried out. On day 5, the 4AA grade embryo was frozen. On days 14 to 21 of the menstrual cycle, ERA, as shown in Figure 1 , was performed along with PRP, where the endometrial thickness was increased to 8 mm. The day before embryo transfer, intralipid infusion was administered intravenously (IV). The infusion is usually given in the arm through a vein; the procedure takes 30 to 60 minutes, depending on the dosage and the patient’s response. Intralipid infusion was given to reduce natural killer (NK) cell activity and enhance endometrial receptivity. The next day, ET was scheduled, where a 4AA grade embryo was transferred to the uterus under ultrasound guidance. After ET, within 24 hours, acupuncture complementary therapy was advised to the patient to increase blood flow. Receptivity of endometrium lining for embryo implantation In order to promote the growth of the uterine lining and enhance implantation, the patient was instructed to take prescription drugs for the next 14 days following the embryo transfer operation, such as 200 mcg of progesterone taken orally. The patient’s pregnancy was verified by a positive beta-human chorionic gonadotropin (β-hCG) test 2 weeks later during scheduled follow-up sessions. The reported value of β-hCG was 1269 mIU/ml.

The inability to conceive after 12 months of consistent, unprotected sexual activity is known as infertility. Infertility in about 85% of couples has a known etiology. Ovulatory dysfunction, male factor infertility, and tubal illness are the most frequent causes of infertility. “Unexplained infertility” affects the 15% of infertile couples that remain. Environmental and lifestyle variables that can negatively impact fertility include obesity and smoking. About 25% of cases of infertility are caused by ovulatory abnormalities; polycystic ovary syndrome is present in 70% of an ovulating woman. A chronic illness that is linked to infertility may also be indicated by infertility. Gonadotropins, clomiphene citrate, and aromatase inhibitors like letrozole are used to stimulate the ovaries or cause ovulation during in vitro fertilization (IVF) cycles.[ 1 ] Ovulation disorder, fallopian tube problems, uterine tumors, and endometriosis are often the main reasons for infertility in women. Traditional methods of treating infertility include assisted reproductive technologies, tubal surgical procedures, and sex hormone therapy (follicle-stimulating hormone, human chorionic gonadotropin, etc.).[ 2 ] According to the World Health Organization (WHO), 50% of infertility problems are caused by male factors, and 9% of couples worldwide have these problems. Infertility in men has been linked to a variety of lifestyle and genetic variables, although around 30% of cases are still believed to be idiopathic. Recent developments in sperm DNA fragmentation (SDF), capacitation, and nanotechnology have clarified these unexplained causes.[ 3 ] The inability to carry or conceive a pregnancy to term affects around 10% of women of reproductive age. Female variables alone are responsible for at least 35% of all cases of infertility and include a variety of factors that can affect ovarian development, oocyte maturation, fertilization competence, and an egg’s capacity for preimplantation development, implantation, and fetal growth.[ 4 ] The menstrual cycle causes the endometrium to undergo intricate regeneration and differentiation, a process that is primarily exclusive to humans but also seen in some old-world monkeys, spiny mice, elephant shrews, and bat species. The upper functionalis and lower basalis are the two main layers of the human endometrium. The external layer, the functional layer of the endometrium, is shed when steroid hormones from the ovaries are withdrawn during menstruation. It also noted that the proliferative phase of women’s menstrual cycle, during which the endometrial layer, glands, stroma, and blood vessels regrow, is the time when this layer of the endometrium is regenerated. After ovulation, the glands alter secretory, elongated, and secretory, while the stromal cells initiate decidualization due to circulating P4.[ 5 ] The ability to implant also depends on two factors, namely, the fetus’s health and the endometrium’s receptiveness. Marking the transfer cycle to a more suitable time when the endometrium is unsuitable for implantation may boost the chances of conception. The study aims to assess the endometrial and subendometrial blood flows assessed by Doppler ultrasound and endometrial volume for impact on endometrial receptivity in frozen embryo transfer (FET) cycles.[ 6 ] Endometrial receptivity analysis (ERA) is a test that helps choose the best time to transfer an embryo to a woman’s uterus and ensure the embryo can implant into the uterine lining, the so-called window of implantation. ERA involves taking a sample of the uterine endometrium and determining which genes are active in the tissue. The ERA is an explorative technique developed for commercial use to predict the receptivity status of the endometrium. It is useful in determining endometrium receptivity or nonreceptivity at the right embryo implant or establishment time. Furthermore, ERA can determine the window of implantation (WOI) time, which may occur in the clinic’s postreceptive or prereceptive proliferative phases. The WOI or refers to a period of time during menses in which the endometrium is most efficient, making it as ready for possibly accepting a blastocyst for implantation.[ 7 ] The immunotherapy type is intralipid, a lipid emulsion prepared from soybean oil. Intralipids have been used routinely for enteral nutrition, especially for patients who cannot take food orally because it is a fat emulsion. Intralipids have other uses apart from being a nutrient source, simply as an energy-giving substance; they also have immunological activity. English studies proved that in the intralipid active phase, soybean oil, in fact, inhibited the cytotoxic natural killer (NK) cell activity of the immunological intralipid, yet the mechanism of action of this therapy is not fully understood.[ 8 ] Many studies show that acupuncture is beneficial to the treatment of female infertility. On the other hand, treatment with electroacupuncture during oocyte aspiration in IVF provides a much higher implantation rate and successful delivery. In another prospective randomly controlled trial, Westergaard and colleagues demonstrated that acupuncture raises the outcome of IVF on the day of ET by a considerable amount. An increase in the PR of IVF treatment by more than half was considered in a meta-analysis of ten RCTs with consideration of acupuncture on the day of ET.[ 9 ]

This case highlights the importance of a comprehensive and individualized approach to treating recurrent implantation failure in patients with multiple reproductive challenges. A thorough investigation revealed contributing factors such as low ovarian reserve, thin endometrial lining, minor intrauterine adhesions, and a displaced implantation window. The treatment strategy incorporated advanced techniques like the GnRH antagonist protocol, ICSI, and ERA, ensuring precise timing for embryo transfer. Complementary therapies, including PRP and intralipid infusion, optimized endometrial receptivity and enhanced implantation potential. Acupuncture was also included to reduce stress and improve uterine blood flow, further supporting the treatment outcome. These integrated interventions addressed the underlying causes of previous failures, leading to a successful pregnancy. This case underscores the value of combining traditional and innovative approaches in assisted reproduction, demonstrating how personalized treatment plans can overcome complex infertility issues and improve outcomes for patients facing significant challenges. There are no conflicts of interest.

Without a gold standard to compare to any of these effects, the ERA test’s challenge of demonstrating the presence of a nonreceptive endometrium and locating the displacement within a few hours using a single tool gene profiling seems insurmountable. It assumes that progesterone manipulation can cover a 12- to 24-hour gap and correct the endometrium.[ 10 ] More recent intravenous lipid emulsions (ILEs) using a different fatty acid source have been developed in the past 10 years. These newer ILEs use medium-chain triglycerides, fish oil, olive oil, and various combinations of two or more oils as their supply of fatty acids, whereas the intralipids use just soybean oil. The most researched ILE is intralipids, although substantial research has also been done on these more recent ILEs, primarily with its application in critically ill patients in the intensive care unit (ICU).[ 11 ] As an essential component of TCM, acupuncture has been used to treat a wide range of illnesses and symptoms. However, due to a lack of contemporary scientific study, acupuncture is also experiencing significant difficulties. These days, several contemporary methods, such as systems biology and fMRI, may be used to study the holistic effects of acupuncture. A deeper understanding is thought to significantly advance acupuncture research and help in the modernization and identification of acupuncture.[ 12 ] By providing a customized method of embryo transfer that may increase implantation success and improve overall pregnancy outcomes, the ERA is a noteworthy development in the area of ART. The ERA enables a more customized timing of embryo transfer by accurately determining the WOI by the examination of gene expression profiles, which is especially advantageous for patients with RIF or a history of failure IVF cycles. Although the ERA has demonstrated potential in clinical practice, there are still issues with it, including as inconsistent outcomes, financial concerns, and continuous discussions about whether it should be used for all IVF patients. However, the ERA is expected to become more significant in reproductive medicine as research advances, providing new opportunities for fertility therapy optimization.[ 13 ] Without a gold standard to compare to any of these effects, the ERA test’s challenge of demonstrating the presence of a nonreceptive endometrium and locating the displacement within a few hours using a single tool gene profiling seems insurmountable. It assumes that progesterone manipulation can cover a 12- to 24-hour gap and correct the endometrium.[ 10 ] More recent intravenous lipid emulsions (ILEs) using a different fatty acid source have been developed in the past 10 years. These newer ILEs use medium-chain triglycerides, fish oil, olive oil, and various combinations of two or more oils as their supply of fatty acids, whereas the intralipids use just soybean oil. The most researched ILE is intralipids, although substantial research has also been done on these more recent ILEs, primarily with its application in critically ill patients in the intensive care unit (ICU).[ 11 ] As an essential component of TCM, acupuncture has been used to treat a wide range of illnesses and symptoms. However, due to a lack of contemporary scientific study, acupuncture is also experiencing significant difficulties. These days, several contemporary methods, such as systems biology and fMRI, may be used to study the holistic effects of acupuncture. A deeper understanding is thought to significantly advance acupuncture research and help in the modernization and identification of acupuncture.[ 12 ] By providing a customized method of embryo transfer that may increase implantation success and improve overall pregnancy outcomes, the ERA is a noteworthy development in the area of ART. The ERA enables a more customized timing of embryo transfer by accurately determining the WOI by the examination of gene expression profiles, which is especially advantageous for patients with RIF or a history of failure IVF cycles. Although the ERA has demonstrated potential in clinical practice, there are still issues with it, including as inconsistent outcomes, financial concerns, and continuous discussions about whether it should be used for all IVF patients. However, the ERA is expected to become more significant in reproductive medicine as research advances, providing new opportunities for fertility therapy optimization.[ 13 ]