The Intricacies of Progesterone as Luteal Phase Support in True Natural Cycle and Modified Natural Cycle Frozen Embryo Transfer Protocols

Globally, there is a paradigm shift towards frozen embryo transfers (FET). The protocols are divided into two categories based on the presence or absence of ovulation: natural cycle (NC) and artificial cycle (AC). Although pregnancy rates appear comparable in most studies, there is emerging evidence suggesting a potential association between AC-FET cycles and adverse obstetrical and perinatal outcomes. Suboptimal endometrial preparation and/or absence of the corpus luteum (CL) has been implicated as a potential aetiology. A shift towards NC-FET protocols has been explicitly propagated in the literature for safer maternal and neonatal outcomes. To optimise the NC-FET cycles with both true NC-FET and modified NC-FET, the role of progesterone as luteal phase support (LPS) is emphasised, though there is no consensus in the literature on using progesterone as LPS in these FET cycles. We provide a review based on the biological rationale and clinical evidence for progesterone as LPS in true NC-FET cycles and modified NC-FET cycles: whether it is required, can serum progesterone levels help in individualising LPS, and is there an optimum point in the luteal phase to begin progesterone supplementation?