ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Molecular and Cellular Reproduction
Low-Dose Letrozole-HMG Regimen Reverses Letrozole-Induced Endometrial Impairment and Improves Frozen Embryo Transfer Outcomes
Provisionally accepted
Zhonglin Xiao1,2
Feng Wang3
Yali Yang2Tianxia Xiao2
Jie Chen2Mengxia Li2Chiawei Chu1
Xiujun Fan2
Jian V Zhang2*- 1City University of Macau, Taipa, Macao, SAR China
- 2Chinese Academy of Sciences Shenzhen Institute of Advanced Technology, Shenzhen, China
- 3Shenzhen Hengsheng Hospital, Shenzhen, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
ABSTRACT Letrozole monotherapy, while effective for ovulation induction, may compromise endometrial receptivity in frozen embryo transfer (FET) cycles due to estrogen suppression. This retrospective cohort study included 5,673 infertile patients undergoing FET with one of the following protocols: low-dose letrozole plus HMG (LeH, n = 2,997), letrozole monotherapy (Le, n = 1,762), or natural cycles (NC, n = 914). Endometrial receptivity was assessed via serum hormone assays, scanning electron microscopy (SEM) of pinopodes on post-ovulation days 3 (D3; pre-FET) and 5 (D5; estimated implantation window), and proteomic analyses of endometrial tissue, uterine fluid, and serum on D3. Clinical outcomes revealed that the LeH group had significantly higher implantation, clinical pregnancy and live birth rates compared to the Le and NC groups, especially among older women. Notably, the Le group led to thinner endometrium, lower estradiol levels, reduced vascularization flow index (VFI), and a lower proportion of receptive-phase endometria (28% vs. 60% in NC). In contrast, the LeH group maintained normal endometrial parameters, and resulted in a high proportion of fully developed pinopodes (84%). Proteomic profiling revealed that the Le group adversely affected processes related to cell adhesion and inflammatory regulation, while the LeH group reversed these alterations. It activated pathways important for embryo implantation and promoted an anti-inflammatory environment. These results suggest that the LeH regimen mitigates letrozole-induced endometrial impairment and enhances FET outcomes through structural, molecular, and immunological mechanisms, offering a promising approach for optimized endometrial preparation.
Keywords: Infertility, Endometrial receptivity, implantation, Pinopode, Frozen embryo transfer, Letrozole, human menopausalgonadotropin, Proteomics
Received: 15 Oct 2025; Accepted: 25 Nov 2025.
Copyright: © 2025 Xiao, Wang, Yang, Xiao, Chen, Li, Chu, Fan and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jian V Zhang
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.