L26/P-333 Impact of subcutaneous progesterone supplementation on reproductive outcomes in women with adenomyosis undergoing frozen embryo transfer: retrospective cohort study

Abstract Study question Can subcutaneous progesterone supplementation compensate for functional progesterone resistance and achieve comparable reproductive outcomes in women with adenomyosis? Summary answer Subcutaneous progesterone supplementation enables women with adenomyosis to achieve reproductive outcomes comparable to controls, although higher progesterone exposure is required, supporting a condition-specific progesterone resistance. What is known already Adequate progesterone exposure during the luteal phase is essential for implantation and early pregnancy maintenance. Adenomyosis has been associated with impaired endometrial receptivity and altered progesterone signaling, leading to the concept of progesterone resistance. However, luteal-phase support protocols are currently standardized and applied uniformly across all patients. Whether intensified progesterone supplementation can compensate for altered progesterone bioavailability in adenomyosis remains unclear. Study design, size, duration This retrospective cohort study included 716 hormone replacement therapy frozen–thawed single blastocyst transfers (HRT-FET) performed between June 2020 and December 2024. Participants/materials, setting, methods Women undergoing HRT-FET with serum progesterone measured at embryo transfer (ET) and at β-hCG were included. To ensure unique observations, only the first ET per patient with available progesterone measurements at both ET and β-hCG was included. Patients with progesterone <10 ng/mL at ET received subcutaneous progesterone supplementation. Progesterone levels and reproductive outcomes were compared between women with adenomyosis and controls. Receiver operating characteristic (ROC) analysis identified progesterone thresholds associated with ongoing pregnancy and miscarriage. Main results and the role of chance Women with adenomyosis required subcutaneous progesterone supplementation more frequently than controls (28.6% vs 19.7%, p = 0.020). Among supplemented patients, progesterone levels at ET were comparable, whereas progesterone at β-hCG was significantly higher in women with adenomyosis (13.5 vs 10.5 ng/mL, p = 0.015), resulting in a greater progesterone increase (ΔP: 5.81 vs 2.57 ng/mL, p = 0.048). Ongoing pregnancy and miscarriage, adjusted for female age and blastocyst quality, were comparable between groups (OR = 0.709, p = 0.353 for ongoing pregnancy and OR = 0.615, p = 0.578 for miscarriage) ROC analysis identified a higher progesterone threshold associated with ongoing pregnancy in adenomyosis compared with controls (17.0 vs 15.7 ng/mL), although discriminative performance for ongoing pregnancy was modest in both groups. Direction-corrected ROC analysis (low progesterone as risk condition) for miscarriage showed greater discriminative ability in adenomyosis (AUC 0.67, 95% CI 0.46–0.88) than in controls (AUC 0.46, 95% CI 0.33–0.59), indicating a stronger role of progesterone in pregnancy maintenance. Notably, despite supplementation, only 25% of women with adenomyosis reached progesterone levels ≥17 ng/mL at β-hCG. Limitations, reasons for caution The retrospective design limits causal inference. Serum progesterone may not fully reflect endometrial tissue exposure, and residual confounding cannot be excluded. Wider implications of the findings These findings support a functional progesterone resistance in adenomyosis and indicate that standard luteal-phase support protocols may be insufficient in this population, as only a minority of women achieve progesterone levels associated with improved reproductive outcomes. Enhanced luteal support strategies may therefore be required to optimize reproductive outcomes. Trial registration number No