Luteal phase support in FET cycles has long been treated as a one-size-fits-all protocol. A growing body of prospective data shows that this approach leaves a substantial subset of patients below the protective serum progesterone threshold — and that better monitoring, multi-route rescue and a gradual shift toward natural-cycle FET could measurably improve outcomes.
In hormone replacement therapy (HRT) FET cycles, the absence of a corpus luteum means that achieved serum progesterone depends entirely on exogenous administration. Multiple prospective studies show that approximately one in three patients on standard vaginal progesterone falls below the protective threshold of 9–10 ng/mL on transfer day — with a measurable drop in ongoing pregnancy rates.
When serum progesterone is below threshold, increasing the vaginal dose does not help — there is a clear absorption ceiling. The evidence supports adding a second route of administration: subcutaneous progesterone, rectal progesterone, or oral dydrogesterone. With multi-route rescue, outcomes are restored to those of patients who reach threshold on standard therapy.
Several patient-level factors increase the risk of low serum progesterone: higher BMI and a non-Lactobacillus-dominant vaginal microbiome both correlate with reduced absorption. Identifying these patients before transfer allows pre-emptive multi-route therapy and shorter time to optimal serum levels.
HRT cycles solve the low-progesterone problem at the cost of substantial medication exposure for all patients to rescue the subset who need it. Emerging data on increased pre-eclampsia risk in artificial cycles (linked to the absence of corpus luteum and its cardio-protective relaxin output) makes a strong case for moving toward natural and modified-natural FET protocols whenever clinically feasible.
Luteal phase support based on serum progesterone monitoring: why standard vaginal therapy fails to reach the protective level in a subset of patients on the hormone replacement cycle, how to define the threshold value on transfer day, and when a change in the route of administration is indicated. Arguments for moving toward natural and modified natural FET cycles.
Luteal phase support based on serum progesterone monitoring: why standard vaginal therapy fails to reach the protective level in a subset of patients on the hormone replacement cycle, how to define the threshold value on transfer day, and when a change in the route of administration is indicated. Arguments for moving toward natural and modified natural FET cycles.
Measure serum progesterone on transfer day with attention to timing of the last dose.
Add a second route of administration when below threshold; do not simply increase vaginal dose.
Identify patients with higher BMI or vaginal dysbiosis at increased risk before transfer.
Use natural cycles when feasible to reduce medication exposure and pre-eclampsia risk.
Gynecologist, reproductive surgeon and researcher at IVI RMA Valencia, specializing in human reproduction and assisted reproductive techniques since 2005. Her research focuses on serum progesterone in embryo transfer cycles and luteal phase management. Associate Professor of Master's programmes in assisted reproduction at the University of Valencia and author of more than 50 scientific papers.
Author of the lecture "Personalized luteal phase support"
