A novel approach to treating Endometriosis-Related Repeated IVF failures- insights from single case report

A 29-year-old nulligravida patient presented with a history of infertility, attributed to peritoneal endometriosis diagnosed four years prior through transvaginal ultrasound and magnetic resonance imaging. Despite having a normal ovarian reserve, regular menstrual cycles, and normal hysterosalpingography findings, she had been unable to conceive after nine cycles of COS with intrauterine insemination and four cycles of IVF treatment. During her IVF attempts, both long GnRH agonist suppression protocols and GnRH antagonist protocols were utilized, with daily follicle-stimulating hormone (FSH) doses ranging from 100 to 175 IU (Table 1 ). These regimens resulted in the retrieval of 4–14 oocytes per cycle; however, embryo transfer rates were suboptimal, with only 0–1 poor-quality embryo available for transfer per cycle. There were no cryopreserved embryos, and all IVF cycles failed to achieve pregnancy. Additionally, her partner’s semen analysis revealed no abnormalities. Table 1 Patient's COS variables during her IVF cycle attempts Cycle # COS protocol Duration of COS (days) Total dose of FSH used during COS Trigger mode # of oocytes # of MII oocytes # of 2PN # of top quality embryos 1 GnRHant pretreatment c' GnRHant protocol 7 850 Dual trigger 4 2 1 0 2 Stop GnRH ag/GnRHant protocol 10 1400 Dual trigger 8 5 4 0 3 GnRHant pretreatment c' GnRHant protocol 9 1275 Dual trigger 12 9 5 0 4 Long GnRHag suppressive protocol 9 1400 hCG trigger 14 14 7 0 5 Dienogest pretreatment c' Stop GnRH ag/GnRHant protocol 12 2225 Dual trigger 16 11 8 3 Patient's COS variables during her IVF cycle attempts Given the history of repeated implantation failure and poor embryo quality, we designed a novel approach comprising three stages: Pre-Stimulation Dienogest Treatment: The patient underwent two months of treatment with Dienogest (Visabelle® 2 mg daily; Bayer, Hod Hasharon, Israel) to suppress the inflammatory environment caused by endometriosis. GnRH-agonist (triptorelin® 0.2 mg)(Ferring, Caesarea, Israel) was started with the last 7 Dienogest pills and discontinued with the onset of menses (Fig. 1 ), after confirmation of downregulation via serum estradiol levels and transvaginal sonography. Fig. 1 The novel COS protocol and the subsequent natural cycle frozen-thawed embryo transfer with modified luteal phase support Controlled ovarian stimulation: COS was initiated with gonadotropins (Pergoveris®, Merck Group, Herzliya, Israel) 200 IU/day. Once the leading follicle had reached a size of 14 mm, Pergoveris was substituted with HP-hMG (Menopur, Ferring, Caesarea, Israel) 225 IU (stepped down to 75) and co-treatment with the GnRH antagonist (cetrorelix, Merck Group, Herzliya, Israel) 0.25 mg/d, was initiated and continued up to and including the day of final follicular maturation trigger. Final follicular maturation was triggered with the co-administration of GnRH agonist (triptorelin 0.2mg) and recombinant hCG 62.5mcg (Ovitrelle, Merck Group, Herzliya, Israel), 35 h prior to OPU (dual trigger) to optimize follicular response. Sixteen oocytes were retrieved, with 11 morphologically mature. Of these, eight fertilized, resulting in the cryopreservation of two high-quality cleaved embryos (AIDA score: 5.7) and one high-quality blastocyst graded 4AA. Natural Cycle Frozen-Thawed Embryo Transfer: In the subsequent natural cycle, the patient was monitored via serial ultrasounds and hormonal assays to confirm ovulation. The implantation window was identified based on the mid-cycle LH surge (70.3 IU/L on cycle day 25), with luteal support initiated the following day using Crinone® vaginal gel (80 mg/day), and dydrogesterone (10 mg three times daily). Recombinant hCG (250 mcg), and GnRH agonist injections 0.1 mg were administered three and seven days post-ovulation. One thawed blastocyst (graded 4AA) was transferred, resulting in a singleton ongoing pregnancy confirmed via ultrasonography. Pre-Stimulation Dienogest Treatment: The patient underwent two months of treatment with Dienogest (Visabelle® 2 mg daily; Bayer, Hod Hasharon, Israel) to suppress the inflammatory environment caused by endometriosis. GnRH-agonist (triptorelin® 0.2 mg)(Ferring, Caesarea, Israel) was started with the last 7 Dienogest pills and discontinued with the onset of menses (Fig. 1 ), after confirmation of downregulation via serum estradiol levels and transvaginal sonography. Fig. 1 The novel COS protocol and the subsequent natural cycle frozen-thawed embryo transfer with modified luteal phase support The novel COS protocol and the subsequent natural cycle frozen-thawed embryo transfer with modified luteal phase support Controlled ovarian stimulation: COS was initiated with gonadotropins (Pergoveris®, Merck Group, Herzliya, Israel) 200 IU/day. Once the leading follicle had reached a size of 14 mm, Pergoveris was substituted with HP-hMG (Menopur, Ferring, Caesarea, Israel) 225 IU (stepped down to 75) and co-treatment with the GnRH antagonist (cetrorelix, Merck Group, Herzliya, Israel) 0.25 mg/d, was initiated and continued up to and including the day of final follicular maturation trigger. Final follicular maturation was triggered with the co-administration of GnRH agonist (triptorelin 0.2mg) and recombinant hCG 62.5mcg (Ovitrelle, Merck Group, Herzliya, Israel), 35 h prior to OPU (dual trigger) to optimize follicular response. Sixteen oocytes were retrieved, with 11 morphologically mature. Of these, eight fertilized, resulting in the cryopreservation of two high-quality cleaved embryos (AIDA score: 5.7) and one high-quality blastocyst graded 4AA. Natural Cycle Frozen-Thawed Embryo Transfer: In the subsequent natural cycle, the patient was monitored via serial ultrasounds and hormonal assays to confirm ovulation. The implantation window was identified based on the mid-cycle LH surge (70.3 IU/L on cycle day 25), with luteal support initiated the following day using Crinone® vaginal gel (80 mg/day), and dydrogesterone (10 mg three times daily). Recombinant hCG (250 mcg), and GnRH agonist injections 0.1 mg were administered three and seven days post-ovulation. One thawed blastocyst (graded 4AA) was transferred, resulting in a singleton ongoing pregnancy confirmed via ultrasonography.

Clinicians managing patients with endometriosis and recurrent failure often face significant challenges in achieving successful IVF outcomes. This case underscores the potential of innovative, combined treatment protocols that include pre-stimulation Dienogest, optimized COS strategies such as the Stop GnRH-agonist/GnRH-antagonist protocol, and precise natural cycle FET with tailored luteal phase support. While this novel approach yielded an improved ovarian response, better embryo quality, and a successful singleton pregnancy, further randomized controlled trials are warranted to evaluate its efficacy and reproducibility. This therapeutic strategy may provide new hope for fertility specialists and their patients in the quest for overcoming endometriosis-related barriers to pregnancy.

Endometriosis represents one of the most challenging conditions in reproductive medicine, significantly impacting IVF outcomes through ovarian dysfunction, systemic inflammation, and impaired implantation potential [ 4 – 6 ]. This case demonstrates the potential of combining Dienogest pretreatment, a "Stop GnRH-agonist/GnRH-antagonist protocol" and a natural cycle FET with modified luteal support to ameliorate outcomes in patients with endometriosis and recurrent IVF failure. Dienogest, a 19-nortestosterone-derived progestin, exerts profound anti-inflammatory effects, including modulation of endometriotic lesions via suppression of cytokine signaling, prostaglandin production, and other pathways linked to systemic inflammation [ 11 ]. Regarding the effects of Dienogest according to different endometriosis phenotypes, it causes a significant reduction in both diameter and volume of ovarian endometriomas, whereas the ovarian reserve appears to be preserved [ 10 ]. Folliculogenesis is a highly intricate and dynamic process, involving crosstalk between multiple endocrine signals and cells, occurring over an estimated duration of more than three months [ 14 , 15 ]. Endometriosis, through its well-documented ability to trigger the release of large quantities of proinflammatory cytokines, contributes to a prolonged state of systemic inflammation [ 16 ]. This persistent inflammatory environment has been shown to interfere with normal folliculogenesis, potentially resulting in impaired oocyte development and the downstream production of low-quality embryos [ 4 ]. In the present case report, an improvement in the proportion of top-quality embryos was observed. This improvement might be attributed to the use of dienogest, known to exert anti-inflammatory effects and modulate the inflammatory microenvironment within endometriotic lesions. It is plausible that the retrieved oocytes in this patient developed in a relatively reduced inflammatory milieu, thereby enhancing gamete quality. Although previous studies investigating the use of dienogest at a dose of 2 mg daily for three months prior to IVF have yielded mixed results [ 17 – 19 ], this case highlights its potential as a valuable adjunct in addressing endometriosis-related infertility when incorporated into a personalized, multifaceted treatment regimen. The Stop GnRH-Agonist/GnRH-Antagonist Protocol: The choice to employ the Stop GnRH-agonist/GnRH-antagonist protocol was based on the ability of mid-luteal GnRH-agonist pretreatment to downregulate the pituitary, synchronize follicular growth and enabling a schedule cycle [ 20 , 21 ]. Moreover, since continuing the GnRH-ag during COS is often associated with a significant increase in the number of gonadotropin ampoules required for achieving adequate follicular development, its cessation might improve ovarian response and avoid the need of increasing the gonadotropin daily dose. GnRH-ag causes suppression of pituitary LH secretion for as long as 10 days after the last dose of the agonist [ 22 ], which, together with the immediate LH suppression provided by the GnRH-ant, will eliminate premature LH surge and may improve the quality of the embryos generated. Moreover, we have already demonstrated that the combined Stop GnRH-ag/GnRH-ant OS protocol is a valuable tool in the armamentarium for treating patients with repeated IVF failures and poor embryos quality [ 13 ]. The dual trigger approach: Co-administration of GnRH agonist and hCG, demonstrated improved oocyte maturation and increased number of mature oocytes, higher fertilization rates and better embryos quality [ 23 ]. Natural FET with Modified Luteal Phase Support: Precise synchronization of the embryo transfer with the physiologic implantation window improves IVF outcomes. Employing a natural cycle FET allows the endometrium to develop under the influence of endogenous hormonal signaling, while modified luteal support ensures optimal progesterone levels to sustain pregnancy [ 24 ]. Luteal-phase GnRH agonist and hCG supplementation may augment corpus luteum functionality and promote angiogenesis and cytokine secretion at the implantation site [ 25 , 26 ]. This multifaceted strategy successfully addressed the unique challenges of endometriosis-related infertility in this patient, highlighting the synergistic effects of Dienogest coupled with the Stop GnRH-agonist/GnRH-antagonist protocol.

In vitro fertilization–embryo transfer (IVF-ET) has revolutionized infertility treatment, yet recurrent implantation failure (RIF) remains a clinical challenge, particularly in patients with endometriosis. RIF, defined as the failure to achieve pregnancy after multiple IVF attempts despite the transfer of high-quality embryos, affects a significant proportion of couples and is associated with an increasing psychological burden [ 1 – 3 ]. Endometriosis, a chronic inflammatory condition characterized by the presence of endometrial-like tissue outside the uterine cavity, has been implicated in. disrupt folliculogenesis, reduce oocyte yield, and negatively affect embryo quality and implantation rates [ 4 ]. Moreover, evidence suggests that advanced stages of endometriosis are associated with the poorest outcomes in assisted reproductive technologies (ART) [ 5 , 6 ]. While conventional controlled ovarian stimulation (COS) protocols have yielded conflicting results in this population. Differences in ongoing pregnancy rates were observed in patients who had undergone laparoscopic endometrioma resection [ 7 ]. A retrospective cohort study of 386 women revealed that GnRH agonist protocols may improve biochemical, clinical pregnancy, and live birth rates in patients with stage I/II endometriosis (42.8% vs. 26.7%). However, no significant differences were found for patients with stage III/IV disease [ 8 ]. Dienogest is a 19-nortestosterone derived progestins, has shown promise in the long-term management of endometriosis-related pain, without affecting ovarian reserve [ 9 , 10 ]. Through its profound impact on the inflammatory microenvironment of endometriotic lesions, Dienogest reduces cytokine production, modulates prostaglandin synthesis, and exerts inhibitory control over abnormal cellular signaling pathways [ 11 ]. Additionally, innovative COS strategies, such as "the Stop GnRH-agonist/ GnRH-antagonist protocol", has demonstrated the potential to improvetop-quality embryos yeild in patients with repeated IVF failure and poor embryo quality, with an acceptable clinical pregnancy rate [ 12 , 13 ]. Here, we report a novel, multidisciplincary approach utilizing Dienogest pretreatment, a "Stop GnRH-agonist/GnRH-antagonist protocol," and a subsequent natural cycle frozen-thawed embryo transfer (FET) with modified luteal phase support to successfully achieve pregnancy in a young patient with endometriosis and repeated IVF failures.

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