Targeted management of adenomyosis: frozen embryo transfer outcomes with GnRH-agonist and letrozole therapy: a case series

The third case involved a 31-year-old woman (G4P1A3) with Arabian (Emirati) ethnicity who presented to our clinic with primary infertility of 3 years. Her AMH level was 7.1 ng/mL, and her BMI was 32.2 kg/m 2 . Her reproductive history included a spontaneous miscarriage at 6 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 Tables  1 and 2  and Figs.  5 and 6 ). Fig. 5 Transvaginal ultrasound image of Case 3 showing diffuse adenomyosis in anterior wall and fundus ( A ) asymmetrical thickening (arrow; B ), hyperechoic islands, fan-shaped shadowing, and translesional vascularity Fig. 6 Diagnostic hysteroscopy image of Case 3 after hormonal suppression ( A , B ) Transvaginal ultrasound image of Case 3 showing diffuse adenomyosis in anterior wall and fundus ( A ) asymmetrical thickening (arrow; B ), hyperechoic islands, fan-shaped shadowing, and translesional vascularity Diagnostic hysteroscopy image of Case 3 after hormonal suppression ( A , B ) 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 3 months of GnRH-a (triptoreline acetate 3.75 mg/monthly) and letrozole 5 mg 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 120 h after starting luteal phase support with vaginal micronized progesterone (Endometrin 100 mg, three times per day) and supplemental intramuscular 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.

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 remains 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 – 6 ]. Surgical correction is often challenging, with limited number of studies to objectively evaluate 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 desensibilization, 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 body mass indexes (BMIs) 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.

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 micronized progesterone for intensive luteal phase support, addressing the inherent progesterone resistance frequently seen in adenomyosis. Ectopic endometrial tissue in adenomyosis is characterized 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 [ 8 , 9 ] is the capability of adenomyotic tissue to produce estrogen autonomously. As observed in Cases 1 and 2, elevated basal estradiol levels after downregulation (Table  3 ) were not due to peripheral estrogen conversion, as the patients 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. Standardized protocols for dose and duration are still lacking [ 12 ]. Table 3 General characteristics of the patients and euploid frozen embryo transfer cycle outcomes Category Case 1 Case 2 Case 3 Age (years) 32 31 31 BMI (kg/m 2 ) 25.33 23.3 32.2 AMH (ng/mL) 7.2 7.79 7.1 AFC ( n ) 24 22 20 Previous eFET cycle No previous eFET One natural cycle and one HRT Decapeptyl 3.75 mg + HRT Endometrial thickness before LPS No previous eFET 8 mm triple line 7.7 mm triple Line P4 day of eET with conventional LPS No previous eFET 9.45 ng/mL 10.63 ng/mL Suppression length: Decapeptyl 3.75 intramuscularly + letrozole 5 mg/day 2 months 2 months 3 months E2 after hormonal suppression 31.71 pg/ml 17.12 pg/mL 5.79 pg/mL Endometrial thickness before LPS 7.9 mm triple line 8 mm triple line 7.9 mm triple line P4 day of eET with intensive LPS 9.79 ng/mL 20.23 ng/mL 7.41 ng/mL Treatment outcome Live birth Live birth Live birth BMI, body mass index; E2, estradiol; P4, progesterone; eET, euploid embryo transfer; LPS, luteal phase support General characteristics of the patients and euploid frozen embryo transfer cycle outcomes BMI, body mass index; E2, estradiol; P4, progesterone; eET, euploid embryo transfer; LPS, luteal phase support 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 optimize 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 ]. However, due to potential severe menopausal symptoms, counseling 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 case series herein. 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, such as 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 (that is, 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 individualized 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.