Comparative analysis of low-dose letrozole versus GnRH agonist on implantation markers and IVF outcomes in symptomatic adenomyosis: a randomized trial

Symptomatic adenomyosis is a known impediment to successful implantation and pregnancy in in vitro fertilization; yet optimal pre-treatment strategic approach remains uncertain. This randomized controlled trial compared the effects of low dose letrozole (2.5 mg, thrice weekly for three-months) and GnRH agonist (3.6 mg/month for three-months) on implantation markers and reproductive outcomes in 156 women with symptomatic diffuse adenomyosis undergoing frozen embryo transfer. Seventy-five women with tubal factor infertility served as controls. Endometrial biopsies during the implantation window were analyzed pre- and post-treatment for key receptivity markers via immunohistochemistry and ELISA. Women with adenomyosis exhibited higher BMI (p = 0.02) and basal estradiol (p = 0.03) than controls. No significant differences in clinical pregnancy (letrozole: 27.9%, GnRHa: 29.9%), live birth (letrozole: 17.7%, GnRHa: 19.5%), and miscarriage rates (letrozole: 22.7%, GnRHa: 21.7%) were observed between treatment groups. Notably, outer myometrial involvement was linked to higher odds of pregnancy outcome (OR 3.26, p = 0.01). Both treatment arms showed improved endometrial expression of PR and integrin αvβ3 (p < 0.01), along with significant downregulation (p < 0.001) of ERα, ERβ, VEGF, and eNOS, suggesting enhanced receptivity. These findings suggest that low dose letrozole may be a viable alternative to GnRHa, with lesion location serving as a critical determinant of reproductive success in adenomyosis.