Targeted Management of Adenomyosis: Frozen Embryo Transfer Outcomes With GNRH-Agonist and Letrozole Therapy

Targeted Management of Adenomyosis: Frozen Embryo Transfer Outcomes With GNRH-Agonist and Letrozole Therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Targeted Management of Adenomyosis: Frozen Embryo Transfer Outcomes With GNRH-Agonist and Letrozole Therapy Maryam Farid Mojtahedi, Laura Melado Vidales², Jonalyn Edades², and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6579011/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective : To apply a combined protocol using GnRH agonists and letrozole for endometrial preparation in patients with severe adenomyosis undergoing frozen euploid single embryo transfer (eFET). Design : Case series. Setting : Tertiary referral in vitro fertilization (IVF) clinic. Patients : Three women with moderate and severe adenomyosis and histories of recurrent IVF failures and miscarriages underwent a combined protocol using GnRH agonists and letrozole and diagnostic hysteroscopy with saline instillation followed by hormonal replacement therapy(HRT) for eFET. Main Outcomes Measures: Implantation rates and ongoing pregnancy outcomes. Results : Our three cases resulted in deliveries at 36 ,38 and 40 weeks. Conclusions : Adenomyosis-related infertility remains a challenge. This case series supports the potential efficacy of hormonal suppression by combining GnRH-a, aromatase inhibitors and diagnostic hysteroscopy with saline irrigation prior to the endometrial preparation for eFET in patients with adenomyosis. This protocol offers a promising alternative for cases unresponsive to standard treatments, although further research is warranted to refine guidelines on treatment duration and dosage. Adenomyosis In Vitro Fertilization Gonadotropin-Releasing Hormone letrozole Introduction Adenomyosis is a condition when endometrial tissue, which typically lines the uterus, invades the uterine myometrial layer. Although approximately one in three patients with adenomyosis remain asymptomatic, many experience symptoms ranging from pelvic pain and infertility to heavy menstrual bleeding, which is the most common manifestation [ 1 ]. Traditionally, adenomyosis was diagnosed primarily through histopathological examination after hysterectomy; however, advances in pelvic imaging, such as magnetic resonance imaging (MRI) and transvaginal ultrasound (TVUS), have enabled earlier and more frequent diagnoses, including among younger patients [ 2 ]. Adenomyosis induces a range of changes within the uterus, including inflammation, abnormal uterine contractility, and adverse effects on fertility, which contribute to a higher risk of infertility and miscarriage. In particular, this condition also negatively impacts fertility treatment outcomes by lowering clinical pregnancy rates, reducing live birth rates, and increasing miscarriage rates following in vitro fertilization (IVF) [ 3 ] [ 4 ] [ 5 ] [ 6 ]. Surgical correction is often challenging, with limited number of studies to evaluate objectively the clinical benefit, requiring considerable expertise.[ 7 ]. Consequently, treatment approaches primarily focus on pharmaceutical interventions that target the hormonal imbalances underlying adenomyosis. Hormonal suppression therapy has emerged as a preferred treatment for patients with adenomyosis, particularly before endometrial preparation for frozen-thawed embryo transfer. However, recent evidence indicates that gonadotropin-releasing hormone agonist (GnRH-a) suppression alone, which suppresses the central axis of steroid production via anterior pituitary desensibilisation, may have limited efficacy in improving IVF outcomes [ 8 ] [ 9 ]. To suppress local steroid production by adenomyotic tissue, new protocols have been developed that combine GnRH-a suppression with aromatase inhibitors to enhance treatment efficacy. Here, we present three cases of adenomyosis in women with normal BMI, who experienced multiple IVF cycles, resulting in recurrent miscarriage. We discuss a protocol combining GnRH-a suppression with letrozole for endometrial preparation during euploid frozen-thawed embryo transfer to explore its potential benefits. Case 1 A 32-year-old woman presented to our clinic in September 2023 with six years of secondary infertility. Her obstetric history included four pregnancies (G4P1A3), all of them achieved after IVF/ICSI treatments: a late miscarriage at 21 weeks in 2014 followed by evacuation and curettage, the birth of a healthy daughter at 39 weeks in 2015, and two biochemical pregnancies after frozen euploid embryo transfers in 2017 and 2018. She had undergone elsewhere five IVF/ICSI cycles and a total of 13 euploid blastocysts transferred (including two fresh and the remainder as frozen transfers under HRT). The thrombophilia and antiphospholipid syndrome panels were negative. The husband’s sperm analysis showed normozoospermia. Transvaginal ultrasound (TVUS) showed diffuse adenomyosis in the posterior uterine wall, including hyperechoic islands, myometrial cysts, and echogenic sub-endometrial glands, with a score of 7 [ 10 ](detailed description in Table 2 , 3 and 4 ). The couple underwent ovarian stimulation for IVF/ICSI using an antagonist protocol with 300 IU rFSH (Gonal-f, Merck). A dual trigger was administered with Triptorelin acetate (Gonapeptyl, 0.3 mg) and uhCG (Choriomon, 2500 IU), and 23 cumulus-oocyte complexes (COCs) were retrieved 36h later, resulting in five euploid blastocysts (PGT-A performed with NGS), which were vitrified. For endometrial preparation, she received Triptorelin acetate (Decapeptyl, 3.75 mg) during the luteal phase, followed by daily letrozole (5 mg) for one month. A second GnRH agonist dose was given after four weeks, with diagnostic « irrigation “hysteroscopy performed prior to HRT initiation. She received estradiol (6 mg/day) for 10 days, resulting in a 7.9 mm triple-lined endometrium. Progesterone (Endometrin 100 mg, TID) was started, with an embryo transfer 120 hours later, supported by additional IM progesterone (100 mg every other day). The patient had a positive pregnancy and delivered a baby boy via cesarean section at 38 weeks. Case 2 The second case involved a 31-year-old woman (G2A2) who presented to our clinic with a 5-year history of primary infertility. Her AMH level was 7.79 ng/mL. She had previously undergone one IVF cycle in another center, resulting in an embryo transfer without PGT-A that ended in an early miscarriage. A second miscarriage occurred in our clinic with HRT protocol. Her BMI was 23.3 kg/m², and she reported regular cycles. Her thrombophilia and antiphospholipid syndrome panels were negative. Her husband’s sperm analysis showed normozoospermia. During the TVUS, a globular uterus with diffuse adenomyosis was observed, with asymmetrical thickening, hyperechoic islands, and junctional zone anomalies, with a score of 6 [ 10 ] (detailed description in Table 2 , 3 and 4 ). The patient then underwent an antagonist IVF cycle with 300 IU rFSH (Gonal-f, Merck) and dual trigger (triptorelin acetate 0.3 mg and uhCG 2500 IU). Forty MII were retrieved, resulting in 13 euploid embryos vitrified. The first euploid frozen embryo transfer (eFET) was planned in a natural cycle, yet unsuccessful. The second eFET was planned under HRT but resulted in a clinical miscarriage. For the third eFET, hormonal suppression was performed following the same protocol as case 1: two doses of GnRH agonist-a plus letrozole 5mg for one month, followed by a diagnostic hysteroscopy before starting HRT. Endometrial thickness of 8.3 mm with a triple-line pattern was confirmed with TVUS, and luteal phase support was performed with vaginal micronised progesterone (Endometrin 100 mg, TID) and progesterone intramuscular 100 mg/48h. A positive pregnancy test confirmed pregnancy and she delivered a healthy baby girl at 40 weeks via cesarean section. Case 3 The third case involved a 31-year-old woman (G4P1A3) who presented to our clinic with primary infertility of three years. Her AMH level was 7.1 ng/mL, and her BMI was 32.2 kg/m². Her reproductive history included a spontaneous miscarriage at six weeks, an early miscarriage after IVF/ICSI cycle, and a late miscarriage after IVF/ICSI cycle at 18 weeks, with treatments performed at another clinic. Her husband’s sperm analysis showed normozoospermia. During the TVUS, diffuse adenomyosis in the anterior wall and fundus was seen, with asymmetrical thickening, hyperechoic islands, fan-shaped shadowing, and translesional vascularity, with a score of 8 [ 10 ] (detailed description in Table 2 , 3 and 4 ). She underwent ovarian stimulation with an antagonist protocol, yielding nine chromosomally normal embryos. An initial single day-5 blastocyst transfer in a downregulated HRT cycle was unsuccessful. A hormonal suppression with three months of GnRH-a (Triptoreline acetate 3.75 mg/monthly) and letrozole 5mg daily was performed, followed by a diagnostic hysteroscopy. Endometrial preparation with HRT 6 mg/day of estradiol was done for 12 days, achieving an endometrial thickness of 7.9 mm with a triple-line pattern. Single eFET was planned 120h after starting luteal phase support with vaginal micronised progesterone (Endometrin 100 mg, TID) and supplemental IM progesterone (100 mg every other day). A positive pregnancy test confirmed the success of the cycle, and the patient delivered a healthy baby boy at 36 weeks via cesarean section. Discussion This case series describes a customized protocol for adenomyotic uteri management involving GnRH agonists, aromatase inhibitors, and office hysteroscopy-based endometrial irrigation prior to initiating HRT for endometrial preparation. This protocol successfully prepared the endometrium for implantation, resulting in improved outcomes. Furthermore, intramuscular progesterone was added to standard vaginal micronised progesterone for intensive luteal phase support, addressing the inherent progesterone resistance frequently seen in adenomyosis. Ectopic endometrial tissue in adenomyosis is characterised by aromatase hyperactivity and impaired estrogen inactivation, resulting in elevated estradiol levels and increased pro-inflammatory cytokine activity ([ 7 ] [ 8 ]. Moreover, adenomyosis demonstrates increased expression of estrogen receptors alongside downregulation of progesterone receptors, further contributing to progesterone resistance [ 9 ][ 10 ]. All patients presented multiple hallmarks of adenomyosis. A notable finding in recent studies [ 9 ] [ 8 ] is the capability of adenomyotic tissue to produce estrogen autonomously. As observed in cases 1 and 2, elevated basal estradiol levels after downregulation (Table 1 ) were not due to peripheral estrogen conversion, as they were not obese, underscoring the unique estrogenic activity of adenomyotic tissue. Hormonal suppression with standard treatments, such as GnRH-a, may not always adequately suppress estradiol levels. As reported by Cozzolino et al. [ 11 ], some patients maintained elevated estradiol concentrations even after multiple GnRH-a injections. However, combining GnRH-a and aromatase inhibitor letrozole demonstrated efficacy in further reducing serum estradiol. Standardised protocols for dose and duration are still lacking [ 12 ]. One crucial variable to consider is monitoring estradiol levels closely and asking patients for symptoms of hot flashes. Basal levels of estradiol after GnRH-a suppression are frequently not reported in previous publications, yet they are essential to optimise treatment efficacy to ensure adequate hormonal suppression [ 11 ]. Regular transvaginal ultrasounds (TVUS) are also recommended to assess uterine size, wall thickness, and adenomyotic changes [ 12 ]. On the other hand, due to potential severe menopausal symptoms, counselling and support are critical for patient adherence, especially given limited data on the treatment's impact during later pregnancy stages, as there are very limited alternatives for patients who cannot tolerate the regimen of hormone suppression. Progesterone resistance, common in adenomyosis, has been linked to increased estrogen receptor expression, downregulating progesterone receptors' expression through epigenetic silencing [ 13 ] [ 14 ]. Consequently, intensive luteal phase support and careful monitoring of progesterone levels before and after the embryo transfer are critical. Notably, all FETs presented here were performed with euploid blastocysts, eliminating aneuploidy as a variable, which is a clear strength for the herein case series. Transferring euploid embryos in such challenging cases is crucial to limit variables that could affect implantation and successful outcomes [ 12 ]. All patients underwent office diagnostic hysteroscopy to evaluate the cervical canal and uterine cavity prior to initiating endometrial preparation with HRT [ 15 ]. In addition to its diagnostic purpose, this procedure offers potential benefits, such as cavity irrigation, which may mechanically remove detrimental anti-adhesive glycoproteins from the endometrial surface. Furthermore, aseptic inflammation of the endometrium seems to trigger immune system modulation and alterations in gene expression, thereby enhancing endometrial receptivity [ 15 ]. Despite the promising results, some questions about this approach still need clarification, like the optimal duration for combination treatment or the patient profiles that will benefit the most. Further research should be encouraged, including close monitoring of hormonal levels and ultrasound response (i.e., shrinkage of the lesions) through the hormonal suppression treatment [ 3 ]. Additionally, including supportive strategies for managing progesterone resistance in adenomyosis seems mandatory, as the quality of evidence is still poor [ 16 ]. Complex cases, especially those involving infertility or recurrent pregnancy loss, require individualised management strategies. Combining GnRH-a with letrozole offers a promising alternative for such patients. However, further research, including well-designed randomized controlled trials (RCTs), is crucial to validate and optimize these protocols, ensuring evidence-based improvements in treatment outcomes. Declarations Disclosures , study funding/competing interest(s) : The authors did not receive support from any organization for the submitted work and have no relevant financial or non-financial interests to disclose. Ethics approval: Ethical approval was obtained (Research Ethics Committee – REFA126-2406-ABU-008-LMV). All participants signed informed consent forms to participate in the study and publication. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Author Contribution Maryam & Laura wrote the main manuscript and reviewed and edited. Jonalyn prepared figures and images and reviewed .Barbara and Human reviewed the manuscript. Acknowledgements: The authors express their gratitude to Ms. Firdous Israel for helping with the ultrasound examinations and organising and facilitating the storage of the images, which contributed significantly to this study. Data availability: The data underlying this article are available in the article and its supplementary material. References G. Leyendecker et al. , “Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study,” Arch. Gynecol. Obstet. , vol. 291, no. 4, pp. 917–932, Apr. 2015, doi: 10.1007/s00404-014-3437-8 . A. M. Badawy, A. M. Elnashar, and A. A. Mosbah, “Aromatase inhibitors or gonadotropin-releasing hormone agonists for the management of uterine adenomyosis: a randomized controlled trial,” Acta Obstet. Gynecol. Scand., vol. 91, no. 4, pp. 489–495, Apr. 2012, doi: 10.1111/j.1600-0412.2012.01350.x . G. Moawad et al. , “Adenomyosis: An Updated Review on Diagnosis and Classification,” J. Clin. Med., vol. 12, no. 14, p. 4828, Jul. 2023, doi: 10.3390/jcm12144828 . M. P. Wendel and E. F. Magann, “The Impact of Adenomyosis on Pregnancy and Pregnancy Outcomes: A Review,” Obstet. Gynecol. Surv. , vol. 77, no. 8, pp. 495–500, Aug. 2022, doi: 10.1097/OGX.0000000000001042 . P. Vercellini, D. Consonni, D. Dridi, B. Bracco, M. P. Frattaruolo, and E. Somigliana, “Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis,” Hum. Reprod., vol. 29, no. 5, pp. 964–977, May 2014, doi: 10.1093/humrep/deu041 . A. Maheshwari and S. Bhattacharya, “Adenomyosis and IVF Outcomes - where we are and where we need to be,” J. Endometr. Pelvic Pain Disord. , vol. 9, no. 3, pp. 180–183, Jul. 2017, doi: 10.5301/jeppd.5000291 . H. Osada, S. Silber, T. Kakinuma, M. Nagaishi, K. Kato, and O. Kato, “Surgical procedure to conserve the uterus for future pregnancy in patients suffering from massive adenomyosis,” Reprod. Biomed. Online , vol. 22, no. 1, pp. 94–99, Jan. 2011, doi: 10.1016/j.rbmo.2010.09.014 . M. Li, L. Xu, H. Zhao, Y. Du, and L. Yan, “Effects of artificial cycles with and without gonadotropin-releasing hormone agonist pretreatment on frozen embryo transfer outcomes in patients with adenomyosis,” Sci. Rep. , vol. 11, no. 1, p. 19326, Sep. 2021, doi: 10.1038/s41598-021-98918-5 . M. Cozzolino, S. Tartaglia, L. Pellegrini, G. Troiano, G. Rizzo, and F. Petraglia, “The Effect of Uterine Adenomyosis on IVF Outcomes: a Systematic Review and Meta-analysis,” Reprod. Sci. , vol. 29, no. 11, pp. 3177–3193, Nov. 2022, doi: 10.1007/s43032-021-00818-6 . L. Lazzeri et al. , “A sonographic classification of adenomyosis: interobserver reproducibility in the evaluation of type and degree of the myometrial involvement,” Fertil. Steril., vol. 110, no. 6, pp. 1154–1161.e3, Nov. 2018, doi: 10.1016/j.fertnstert.2018.06.031 . M. Cozzolino, N. Pellicer, D. Galliano, and A. Pellicer, “Pituitary suppression with GnRH agonists before ART may be insufficient to treat women with severe adenomyosis,” Reprod. Biomed. Online, vol. 46, no. 1, pp. 150–155, Jan. 2023, doi: 10.1016/j.rbmo.2022.09.023 . M. Cozzolino et al. , “The first Lugano workshop on the role of adenomyosis in ART,” Reprod. Biomed. Online, p. 104444, Sep. 2024, doi: 10.1016/j.rbmo.2024.104444 . T. Hiraoka, Y. Hirota, and Y. Osuga, “How does adenomyosis impact endometrial receptivity? An updated systematic review of clinical and molecular insights,” FS Rev., vol. 4, no. 1, pp. 15–25, Jan. 2023, doi: 10.1016/j.xfnr.2022.11.004 . J. Nie, X. Liu, and S.-W. Guo, “Promoter Hypermethylation of Progesterone Receptor Isoform B (PR-B) in Adenomyosis and Its Rectification by a Histone Deacetylase Inhibitor and a Demethylation Agent,” Reprod. Sci. , vol. 17, no. 11, pp. 995–1005, Nov. 2010, doi: 10.1177/1933719110377118 . M. Ghasemi, A. Aleyasin, H. M. Fatemi, F. Ghaemdoust, and M. Shahrakipour, “Uterine Cavity Irrigation With Office Hysteroscopy During Ovarian Stimulation for IVF: A Randomized Controlled Trial,” Front. Endocrinol., vol. 13, p. 778988, 2022, doi: 10.3389/fendo.2022.778988 . P. Pirtea, D. De Ziegler, and J. M. Ayoubi, “Endometrial receptivity in adenomyosis and/or endometriosis,” Fertil. Steril., vol. 119, no. 5, pp. 741–745, May 2023, doi: 10.1016/j.fertnstert.2023.03.004 . T. Van Den Bosch et al. , “Sonographic classification and reporting system for diagnosing adenomyosis,” Ultrasound Obstet. Gynecol., vol. 53, no. 5, pp. 576–582, May 2019, doi: 10.1002/uog.19096 . Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6579011","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":457202824,"identity":"3e17415d-fa3a-4509-9492-586fed924711","order_by":0,"name":"Maryam Farid Mojtahedi","email":"data:image/png;base64,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","orcid":"","institution":"ART Fertility Clinic","correspondingAuthor":true,"prefix":"","firstName":"Maryam","middleName":"Farid","lastName":"Mojtahedi","suffix":""},{"id":457202825,"identity":"0f49f603-9165-4c64-a267-fc4eca862de1","order_by":1,"name":"Laura Melado Vidales²","email":"","orcid":"","institution":"ART Fertility Clinic","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"Melado","lastName":"Vidales²","suffix":""},{"id":457202826,"identity":"4cc7728a-7b4e-4335-8506-618a12561ea8","order_by":2,"name":"Jonalyn Edades²","email":"","orcid":"","institution":"ART Fertility Clinic","correspondingAuthor":false,"prefix":"","firstName":"Jonalyn","middleName":"","lastName":"Edades²","suffix":""},{"id":457202827,"identity":"8762ef96-603e-4721-8af9-e7f01562917e","order_by":3,"name":"Barbara lawrenz","email":"","orcid":"","institution":"ART Fertility Clinic","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"lawrenz","suffix":""},{"id":457202829,"identity":"e2b107ad-8eec-496c-86a6-fb1d4ee974eb","order_by":4,"name":"Human M Fatemi","email":"","orcid":"","institution":"ART Fertility Clinic","correspondingAuthor":false,"prefix":"","firstName":"Human","middleName":"M","lastName":"Fatemi","suffix":""}],"badges":[],"createdAt":"2025-05-02 14:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6579011/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6579011/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89505515,"identity":"43462431-af74-4cd1-96c1-9f391eb91cd9","added_by":"auto","created_at":"2025-08-20 17:01:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":406257,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6579011/v1/d667e87d-2ed5-4a17-afd3-af71f4f8c8e3.pdf"},{"id":82884065,"identity":"549f7029-f043-45b5-abaa-13676e41c674","added_by":"auto","created_at":"2025-05-16 11:31:08","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8130078,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6579011/v1/95d1467cedc6ef1eed342d43.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eTargeted Management of Adenomyosis: Frozen Embryo Transfer Outcomes With GNRH-Agonist and Letrozole Therapy\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdenomyosis is a condition when endometrial tissue, which typically lines the uterus, invades the uterine myometrial layer. Although approximately one in three patients with adenomyosis remain asymptomatic, many experience symptoms ranging from pelvic pain and infertility to heavy menstrual bleeding, which is the most common manifestation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Traditionally, adenomyosis was diagnosed primarily through histopathological examination after hysterectomy; however, advances in pelvic imaging, such as magnetic resonance imaging (MRI) and transvaginal ultrasound (TVUS), have enabled earlier and more frequent diagnoses, including among younger patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdenomyosis induces a range of changes within the uterus, including inflammation, abnormal uterine contractility, and adverse effects on fertility, which contribute to a higher risk of infertility and miscarriage. In particular, this condition also negatively impacts fertility treatment outcomes by lowering clinical pregnancy rates, reducing live birth rates, and increasing miscarriage rates following in vitro fertilization (IVF) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Surgical correction is often challenging, with limited number of studies to evaluate objectively the clinical benefit, requiring considerable expertise.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, treatment approaches primarily focus on pharmaceutical interventions that target the hormonal imbalances underlying adenomyosis. Hormonal suppression therapy has emerged as a preferred treatment for patients with adenomyosis, particularly before endometrial preparation for frozen-thawed embryo transfer. However, recent evidence indicates that gonadotropin-releasing hormone agonist (GnRH-a) suppression alone, which suppresses the central axis of steroid production via anterior pituitary desensibilisation, may have limited efficacy in improving IVF outcomes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. To suppress local steroid production by adenomyotic tissue, new protocols have been developed that combine GnRH-a suppression with aromatase inhibitors to enhance treatment efficacy.\u003c/p\u003e \u003cp\u003eHere, we present three cases of adenomyosis in women with normal BMI, who experienced multiple IVF cycles, resulting in recurrent miscarriage. We discuss a protocol combining GnRH-a suppression with letrozole for endometrial preparation during euploid frozen-thawed embryo transfer to explore its potential benefits.\u003c/p\u003e"},{"header":"Case 1","content":"\u003cp\u003eA 32-year-old woman presented to our clinic in September 2023 with six years of secondary infertility. Her obstetric history included four pregnancies (G4P1A3), all of them achieved after IVF/ICSI treatments: a late miscarriage at 21 weeks in 2014 followed by evacuation and curettage, the birth of a healthy daughter at 39 weeks in 2015, and two biochemical pregnancies after frozen euploid embryo transfers in 2017 and 2018. She had undergone elsewhere five IVF/ICSI cycles and a total of 13 euploid blastocysts transferred (including two fresh and the remainder as frozen transfers under HRT). The thrombophilia and antiphospholipid syndrome panels were negative. The husband\u0026rsquo;s sperm analysis showed normozoospermia. Transvaginal ultrasound (TVUS) showed diffuse adenomyosis in the posterior uterine wall, including hyperechoic islands, myometrial cysts, and echogenic sub-endometrial glands, with a score of 7 [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e](detailed description in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e ,\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe couple underwent ovarian stimulation for IVF/ICSI using an antagonist protocol with 300 IU rFSH (Gonal-f, Merck). A dual trigger was administered with Triptorelin acetate (Gonapeptyl, 0.3 mg) and uhCG (Choriomon, 2500 IU), and 23 cumulus-oocyte complexes (COCs) were retrieved 36h later, resulting in five euploid blastocysts (PGT-A performed with NGS), which were vitrified.\u003c/p\u003e\n\u003cp\u003eFor endometrial preparation, she received Triptorelin acetate (Decapeptyl, 3.75 mg) during the luteal phase, followed by daily letrozole (5 mg) for one month. A second GnRH agonist dose was given after four weeks, with diagnostic \u0026laquo; irrigation \u0026ldquo;hysteroscopy performed prior to HRT initiation. She received estradiol (6 mg/day) for 10 days, resulting in a 7.9 mm triple-lined endometrium. Progesterone (Endometrin 100 mg, TID) was started, with an embryo transfer 120 hours later, supported by additional IM progesterone (100 mg every other day). The patient had a positive pregnancy and delivered a baby boy via cesarean section at 38 weeks.\u003c/p\u003e"},{"header":"Case 2","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cp\u003eThe second case involved a 31-year-old woman (G2A2) who presented to our clinic with a 5-year history of primary infertility. Her AMH level was 7.79 ng/mL. She had previously undergone one IVF cycle in another center, resulting in an embryo transfer without PGT-A that ended in an early miscarriage. A second miscarriage occurred in our clinic with HRT protocol. Her BMI was 23.3 kg/m\u0026sup2;, and she reported regular cycles. Her thrombophilia and antiphospholipid syndrome panels were negative. Her husband\u0026rsquo;s sperm analysis showed normozoospermia. During the TVUS, a globular uterus with diffuse adenomyosis was observed, with asymmetrical thickening, hyperechoic islands, and junctional zone anomalies, with a score of 6 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] (detailed description in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e,\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe patient then underwent an antagonist IVF cycle with 300 IU rFSH (Gonal-f, Merck) and dual trigger (triptorelin acetate 0.3 mg and uhCG 2500 IU). Forty MII were retrieved, resulting in 13 euploid embryos vitrified.\u003c/p\u003e \u003cp\u003eThe first euploid frozen embryo transfer (eFET) was planned in a natural cycle, yet unsuccessful. The second eFET was planned under HRT but resulted in a clinical miscarriage. For the third eFET, hormonal suppression was performed following the same protocol as case 1: two doses of GnRH agonist-a plus letrozole 5mg for one month, followed by a diagnostic hysteroscopy before starting HRT. Endometrial thickness of 8.3 mm with a triple-line pattern was confirmed with TVUS, and luteal phase support was performed with vaginal micronised progesterone (Endometrin 100 mg, TID) and progesterone intramuscular 100 mg/48h. A positive pregnancy test confirmed pregnancy and she delivered a healthy baby girl at 40 weeks via cesarean section.\u003c/p\u003e \u003c/div\u003e"},{"header":"Case 3","content":"\u003cp\u003eThe third case involved a 31-year-old woman (G4P1A3) who presented to our clinic with primary infertility of three years. Her AMH level was 7.1 ng/mL, and her BMI was 32.2 kg/m\u0026sup2;.\u003c/p\u003e \u003cp\u003eHer reproductive history included a spontaneous miscarriage at six weeks, an early miscarriage after IVF/ICSI cycle, and a late miscarriage after IVF/ICSI cycle at 18 weeks, with treatments performed at another clinic. Her husband\u0026rsquo;s sperm analysis showed normozoospermia. During the TVUS, diffuse adenomyosis in the anterior wall and fundus was seen, with asymmetrical thickening, hyperechoic islands, fan-shaped shadowing, and translesional vascularity, with a score of 8 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] (detailed description in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e ,\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eShe underwent ovarian stimulation with an antagonist protocol, yielding nine chromosomally normal embryos. An initial single day-5 blastocyst transfer in a downregulated HRT cycle was unsuccessful. A hormonal suppression with three months of GnRH-a (Triptoreline acetate 3.75 mg/monthly) and letrozole 5mg daily was performed, followed by a diagnostic hysteroscopy. Endometrial preparation with HRT 6 mg/day of estradiol was done for 12 days, achieving an endometrial thickness of 7.9 mm with a triple-line pattern. Single eFET was planned 120h after starting luteal phase support with vaginal micronised progesterone (Endometrin 100 mg, TID) and supplemental IM progesterone (100 mg every other day). A positive pregnancy test confirmed the success of the cycle, and the patient delivered a healthy baby boy at 36 weeks via cesarean section.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case series describes a customized protocol for adenomyotic uteri management involving GnRH agonists, aromatase inhibitors, and office hysteroscopy-based endometrial irrigation prior to initiating HRT for endometrial preparation. This protocol successfully prepared the endometrium for implantation, resulting in improved outcomes. Furthermore, intramuscular progesterone was added to standard vaginal micronised progesterone for intensive luteal phase support, addressing the inherent progesterone resistance frequently seen in adenomyosis. Ectopic endometrial tissue in adenomyosis is characterised by aromatase hyperactivity and impaired estrogen inactivation, resulting in elevated estradiol levels and increased pro-inflammatory cytokine activity ([\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e] [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Moreover, adenomyosis demonstrates increased expression of estrogen receptors alongside downregulation of progesterone receptors, further contributing to progesterone resistance [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eAll patients presented multiple hallmarks of adenomyosis. A notable finding in recent studies [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e] [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e] is the capability of adenomyotic tissue to produce estrogen autonomously. As observed in cases 1 and 2, elevated basal estradiol levels after downregulation (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) were not due to peripheral estrogen conversion, as they were not obese, underscoring the unique estrogenic activity of adenomyotic tissue. Hormonal suppression with standard treatments, such as GnRH-a, may not always adequately suppress estradiol levels. As reported by Cozzolino et al. [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e], some patients maintained elevated estradiol concentrations even after multiple GnRH-a injections. However, combining GnRH-a and aromatase inhibitor letrozole demonstrated efficacy in further reducing serum estradiol. Standardised protocols for dose and duration are still lacking [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eOne crucial variable to consider is monitoring estradiol levels closely and asking patients for symptoms of hot flashes. Basal levels of estradiol after GnRH-a suppression are frequently not reported in previous publications, yet they are essential to optimise treatment efficacy to ensure adequate hormonal suppression [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. Regular transvaginal ultrasounds (TVUS) are also recommended to assess uterine size, wall thickness, and adenomyotic changes [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. On the other hand, due to potential severe menopausal symptoms, counselling and support are critical for patient adherence, especially given limited data on the treatment\u0026apos;s impact during later pregnancy stages, as there are very limited alternatives for patients who cannot tolerate the regimen of hormone suppression.\u003c/p\u003e\n\u003cp\u003eProgesterone resistance, common in adenomyosis, has been linked to increased estrogen receptor expression, downregulating progesterone receptors\u0026apos; expression through epigenetic silencing [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e] [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. Consequently, intensive luteal phase support and careful monitoring of progesterone levels before and after the embryo transfer are critical. Notably, all FETs presented here were performed with euploid blastocysts, eliminating aneuploidy as a variable, which is a clear strength for the herein case series. Transferring euploid embryos in such challenging cases is crucial to limit variables that could affect implantation and successful outcomes [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eAll patients underwent office diagnostic hysteroscopy to evaluate the cervical canal and uterine cavity prior to initiating endometrial preparation with HRT [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. In addition to its diagnostic purpose, this procedure offers potential benefits, such as cavity irrigation, which may mechanically remove detrimental anti-adhesive glycoproteins from the endometrial surface. Furthermore, aseptic inflammation of the endometrium seems to trigger immune system modulation and alterations in gene expression, thereby enhancing endometrial receptivity [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eDespite the promising results, some questions about this approach still need clarification, like the optimal duration for combination treatment or the patient profiles that will benefit the most. Further research should be encouraged, including close monitoring of hormonal levels and ultrasound response (i.e., shrinkage of the lesions) through the hormonal suppression treatment [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. Additionally, including supportive strategies for managing progesterone resistance in adenomyosis seems mandatory, as the quality of evidence is still poor [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. Complex cases, especially those involving infertility or recurrent pregnancy loss, require individualised management strategies. Combining GnRH-a with letrozole offers a promising alternative for such patients. However, further research, including well-designed randomized controlled trials (RCTs), is crucial to validate and optimize these protocols, ensuring evidence-based improvements in treatment outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDisclosures\u003c/h2\u003e \u003cp\u003e, \u003cb\u003estudy funding/competing interest(s)\u003c/b\u003e: The authors did not receive support from any organization for the submitted work and have no relevant financial or non-financial interests to disclose.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval:\u003c/strong\u003e \u003cp\u003eEthical approval was obtained (Research Ethics Committee \u0026ndash; REFA126-2406-ABU-008-LMV). All participants signed informed consent forms to participate in the study and publication.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConflict of interest\u003c/h2\u003e \u003cp\u003eOn behalf of all authors, the corresponding author states that there is no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMaryam \u0026amp; Laura wrote the main manuscript and reviewed and edited. Jonalyn prepared figures and images and reviewed .Barbara and Human reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThe authors express their gratitude to Ms. Firdous Israel for helping with the ultrasound examinations and organising and facilitating the storage of the images, which contributed significantly to this study.\u003c/p\u003e\u003ch2\u003eData availability:\u003c/h2\u003e \u003cp\u003eThe data underlying this article are available in the article and its supplementary material.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eG. Leyendecker \u003cem\u003eet al.\u003c/em\u003e, \u0026ldquo;Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study,\u0026rdquo; \u003cem\u003eArch. Gynecol. Obstet.\u003c/em\u003e, vol. 291, no. 4, pp. 917\u0026ndash;932, Apr. 2015, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00404-014-3437-8\u003c/span\u003e\u003cspan address=\"10.1007/s00404-014-3437-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA. M. Badawy, A. M. Elnashar, and A. A. Mosbah, \u0026ldquo;Aromatase inhibitors or gonadotropin-releasing hormone agonists for the management of uterine adenomyosis: a randomized controlled trial,\u0026rdquo; Acta Obstet. Gynecol. Scand., vol. 91, no. 4, pp. 489\u0026ndash;495, Apr. 2012, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1600-0412.2012.01350.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1600-0412.2012.01350.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG. Moawad \u003cem\u003eet al.\u003c/em\u003e, \u0026ldquo;Adenomyosis: An Updated Review on Diagnosis and Classification,\u0026rdquo; J. Clin. Med., vol. 12, no. 14, p. 4828, Jul. 2023, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jcm12144828\u003c/span\u003e\u003cspan address=\"10.3390/jcm12144828\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM. P. Wendel and E. F. Magann, \u0026ldquo;The Impact of Adenomyosis on Pregnancy and Pregnancy Outcomes: A Review,\u0026rdquo; \u003cem\u003eObstet. Gynecol. Surv.\u003c/em\u003e, vol. 77, no. 8, pp. 495\u0026ndash;500, Aug. 2022, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/OGX.0000000000001042\u003c/span\u003e\u003cspan address=\"10.1097/OGX.0000000000001042\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP. Vercellini, D. Consonni, D. Dridi, B. Bracco, M. P. Frattaruolo, and E. Somigliana, \u0026ldquo;Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis,\u0026rdquo; Hum. Reprod., vol. 29, no. 5, pp. 964\u0026ndash;977, May 2014, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/humrep/deu041\u003c/span\u003e\u003cspan address=\"10.1093/humrep/deu041\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA. Maheshwari and S. Bhattacharya, \u0026ldquo;Adenomyosis and IVF Outcomes - where we are and where we need to be,\u0026rdquo; \u003cem\u003eJ. Endometr. Pelvic Pain Disord.\u003c/em\u003e, vol. 9, no. 3, pp. 180\u0026ndash;183, Jul. 2017, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5301/jeppd.5000291\u003c/span\u003e\u003cspan address=\"10.5301/jeppd.5000291\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eH. Osada, S. Silber, T. Kakinuma, M. Nagaishi, K. Kato, and O. Kato, \u0026ldquo;Surgical procedure to conserve the uterus for future pregnancy in patients suffering from massive adenomyosis,\u0026rdquo; \u003cem\u003eReprod. Biomed. Online\u003c/em\u003e, vol. 22, no. 1, pp. 94\u0026ndash;99, Jan. 2011, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.rbmo.2010.09.014\u003c/span\u003e\u003cspan address=\"10.1016/j.rbmo.2010.09.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM. Li, L. Xu, H. Zhao, Y. Du, and L. Yan, \u0026ldquo;Effects of artificial cycles with and without gonadotropin-releasing hormone agonist pretreatment on frozen embryo transfer outcomes in patients with adenomyosis,\u0026rdquo; \u003cem\u003eSci. Rep.\u003c/em\u003e, vol. 11, no. 1, p. 19326, Sep. 2021, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-021-98918-5\u003c/span\u003e\u003cspan address=\"10.1038/s41598-021-98918-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM. Cozzolino, S. Tartaglia, L. Pellegrini, G. Troiano, G. Rizzo, and F. Petraglia, \u0026ldquo;The Effect of Uterine Adenomyosis on IVF Outcomes: a Systematic Review and Meta-analysis,\u0026rdquo; \u003cem\u003eReprod. Sci.\u003c/em\u003e, vol. 29, no. 11, pp. 3177\u0026ndash;3193, Nov. 2022, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s43032-021-00818-6\u003c/span\u003e\u003cspan address=\"10.1007/s43032-021-00818-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eL. Lazzeri \u003cem\u003eet al.\u003c/em\u003e, \u0026ldquo;A sonographic classification of adenomyosis: interobserver reproducibility in the evaluation of type and degree of the myometrial involvement,\u0026rdquo; Fertil. Steril., vol. 110, no. 6, pp. 1154\u0026ndash;1161.e3, Nov. 2018, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.fertnstert.2018.06.031\u003c/span\u003e\u003cspan address=\"10.1016/j.fertnstert.2018.06.031\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM. Cozzolino, N. Pellicer, D. Galliano, and A. Pellicer, \u0026ldquo;Pituitary suppression with GnRH agonists before ART may be insufficient to treat women with severe adenomyosis,\u0026rdquo; Reprod. Biomed. Online, vol. 46, no. 1, pp. 150\u0026ndash;155, Jan. 2023, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.rbmo.2022.09.023\u003c/span\u003e\u003cspan address=\"10.1016/j.rbmo.2022.09.023\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM. Cozzolino \u003cem\u003eet al.\u003c/em\u003e, \u0026ldquo;The first Lugano workshop on the role of adenomyosis in ART,\u0026rdquo; Reprod. Biomed. Online, p. 104444, Sep. 2024, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.rbmo.2024.104444\u003c/span\u003e\u003cspan address=\"10.1016/j.rbmo.2024.104444\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eT. Hiraoka, Y. Hirota, and Y. Osuga, \u0026ldquo;How does adenomyosis impact endometrial receptivity? An updated systematic review of clinical and molecular insights,\u0026rdquo; FS Rev., vol. 4, no. 1, pp. 15\u0026ndash;25, Jan. 2023, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.xfnr.2022.11.004\u003c/span\u003e\u003cspan address=\"10.1016/j.xfnr.2022.11.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ. Nie, X. Liu, and S.-W. Guo, \u0026ldquo;Promoter Hypermethylation of Progesterone Receptor Isoform B (PR-B) in Adenomyosis and Its Rectification by a Histone Deacetylase Inhibitor and a Demethylation Agent,\u0026rdquo; \u003cem\u003eReprod. Sci.\u003c/em\u003e, vol. 17, no. 11, pp. 995\u0026ndash;1005, Nov. 2010, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/1933719110377118\u003c/span\u003e\u003cspan address=\"10.1177/1933719110377118\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM. Ghasemi, A. Aleyasin, H. M. Fatemi, F. Ghaemdoust, and M. Shahrakipour, \u0026ldquo;Uterine Cavity Irrigation With Office Hysteroscopy During Ovarian Stimulation for IVF: A Randomized Controlled Trial,\u0026rdquo; Front. Endocrinol., vol. 13, p. 778988, 2022, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fendo.2022.778988\u003c/span\u003e\u003cspan address=\"10.3389/fendo.2022.778988\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP. Pirtea, D. De Ziegler, and J. M. Ayoubi, \u0026ldquo;Endometrial receptivity in adenomyosis and/or endometriosis,\u0026rdquo; Fertil. Steril., vol. 119, no. 5, pp. 741\u0026ndash;745, May 2023, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.fertnstert.2023.03.004\u003c/span\u003e\u003cspan address=\"10.1016/j.fertnstert.2023.03.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eT. Van Den Bosch \u003cem\u003eet al.\u003c/em\u003e, \u0026ldquo;Sonographic classification and reporting system for diagnosing adenomyosis,\u0026rdquo; Ultrasound Obstet. Gynecol., vol. 53, no. 5, pp. 576\u0026ndash;582, May 2019, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/uog.19096\u003c/span\u003e\u003cspan address=\"10.1002/uog.19096\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Adenomyosis, In Vitro Fertilization, Gonadotropin-Releasing Hormone, letrozole","lastPublishedDoi":"10.21203/rs.3.rs-6579011/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6579011/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: To apply a combined protocol using GnRH agonists and letrozole for endometrial preparation in patients with severe adenomyosis undergoing frozen euploid single embryo transfer (eFET).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e: Case series.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSetting\u003c/strong\u003e: Tertiary referral in vitro fertilization (IVF) clinic.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e: Three women with moderate and severe adenomyosis and histories of recurrent IVF failures and miscarriages underwent a combined protocol using GnRH agonists and letrozole and diagnostic hysteroscopy with saline instillation followed by hormonal replacement therapy(HRT) for eFET.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain Outcomes Measures: \u003c/strong\u003eImplantation rates and ongoing pregnancy outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Our three cases resulted in deliveries at 36 ,38 and 40 weeks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Adenomyosis-related infertility remains a challenge. This case series supports the potential efficacy of hormonal suppression by combining GnRH-a, aromatase inhibitors and diagnostic hysteroscopy with saline irrigation prior to the endometrial preparation for eFET in patients with adenomyosis. This protocol offers a promising alternative for cases unresponsive to standard treatments, although further research is warranted to refine guidelines on treatment duration and dosage.\u003c/p\u003e","manuscriptTitle":"Targeted Management of Adenomyosis: Frozen Embryo Transfer Outcomes With GNRH-Agonist and Letrozole Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-16 11:31:04","doi":"10.21203/rs.3.rs-6579011/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f7f9e57e-20f7-4513-8dd4-35f3188a9499","owner":[],"postedDate":"May 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-20T16:53:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-16 11:31:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6579011","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6579011","identity":"rs-6579011","version":["v1"]},"buildId":"WvIrzKhiLBfengagbw6Ux","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}