A 2026 review and meta-analysis explored ways to optimize natural FETs, examining ovulation timing, progesterone use, luteinized unruptured follicles, and cycle variability across natural, modified natural, and newer natural proliferative phase approaches.
Frozen embryo transfers (FET) need to be timed so the embryo is transferred when the endometrium is ready. This can be done with a medicated cycle, where hormones control timing, or a natural cycle, where the body’s own hormones are used.
Natural cycles are popular because they’re more physiological, but they’re also harder to manage. There’s no clear consensus on how to perform them, and several key issues come up:
- Luteinized unruptured follicle (LUF): In some cycles, the follicle goes through the hormonal changes of ovulation but doesn’t actually release the egg. This can make timing less reliable and may affect outcomes.
- Ovulation timing: Clinics use different methods (LH surge, progesterone rise, ultrasound), but it’s not clear which is best or how precise timing needs to be.
- Luteal phase support (progesterone): Some clinics use it routinely, others don’t, and the evidence has been inconsistent.
- Cycle variability: Factors like hormone levels, follicle size, and endometrial thickness vary from cycle to cycle, and it’s not clear which of these actually matter for success.
Because of these issues, natural FETs can be seen as less predictable than medicated FETs.
In a systematic review and meta-analysis, Erden et al. (2026) combined the results of 70 studies to better understand how natural FETs should be performed and which factors actually affect outcomes for true natural FETs, modified natural FETs, and for a new hybrid approached called natural proliferative phase (NPP) FET.
For more background, see my post Comparing frozen embryo transfer/FET protocols.
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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Optimizing true natural FETs
First, the researchers looked at results for true natural cycles, where ovulation occurs spontaneously and is timed using hormonal monitoring and/or ultrasound.
Luteinized unruptured follicle (LUF), where the follicle undergoes hormonal changes but doesn’t release an egg:
- They measured the prevalence of LUF based on 5 studies, finding that it occurred in about 13% of cycles.
- Cycles where ovulation occurred had a 16% higher relative live birth rate compared to cycles with LUF (relative risk [95% CI]: 1.16 [1.04–1.29], 3 non-randomized studies, I2= 0%). However, when adjusted data from two studies were analyzed, this difference was no longer statistically significant.
- Other studies didn’t find a significant difference in outcomes between LUF and ovulatory cycles.
- The authors note these results should be interpreted with caution, and it’s not clear whether LUF cycles should be cancelled or managed with extra progesterone.
Luteal phase support, where progesterone is given after ovulation to support implantation
- Vaginal progesterone led to a 43% higher relative live birth rate compared to no luteal support (relative risk [95% CI]: 1.43 [1.16–1.78], 2 RCTs, I2= 0%).
- Other studies showed mixed results, with some suggesting benefit and others showing no effect or possible harm.
- The optimal time to start luteal support isn’t clear.
Other findings from reviewing studies (no meta-analysis):
- Different methods of ovulation timing (LH surge, progesterone rise, ultrasound) generally similar but inconsistent. LH-based timing has limitations, as the LH surge doesn’t always align with ovulation, which can affect how precisely transfer is timed. A rise in progesterone may be a more reliable way to identify ovulation, but the exact threshold, such as 1.0 or 1.5 ng/ml, is still unclear.
- No clear threshold of endometrial thickness was associated with reduced live birth rates.
- Endometrial compaction showed conflicting results
- Mid-luteal progesterone levels showed conflicting results
- Rescue progesterone supplementation for low mid-luteal levels didn’t improve outcomes
- No significant association was found between elevated progesterone before ovulation and outcomes
- Higher estradiol levels before ovulation (>100 pg/ml sustained >4 days) were associated with improved live birth rates
Optimizing modified natural FETs
Next, the researchers looked at modified natural cycles, where ovulation is triggered to better control timing.
Luteal phase support
- Vaginal progesterone didn’t improve live birth rates compared to no luteal support (relative risk [95% CI]: 1.04 [0.82–1.32], 2 RCTs, I2= 0%)
- Another RCT using intramuscular progesterone found no benefit, while non-randomized studies found mixed results
- Additional studies also showed no benefit of luteal phase support regardless of progesterone type, timing of initiation, or combination with hCG or GnRH
Other findings from reviewing studies (no meta-analysis):
- Although ovulation is generally triggered when the dominant follicle is around 17 mm, varying follicle sizes (13–22 mm) resulted in comparable reproductive outcomes when endometrial thickness was adequate and progesterone was low
- Transfer timing after trigger: an RCT showed similar live birth rates when embryo transfer was performed at hCG +6 vs +7 days, while a non-randomized study found best outcomes at 160 h
- Higher estradiol at trigger was linked to improved outcomes in some studies
- LH levels at trigger were generally not associated with outcomes
- Progesterone at trigger showed inconsistent effects, with some studies suggesting worse outcomes at higher levels
- Endometrial thickness showed mixed results (one study found no difference, another found decreased live births for thickness 8.0 mm or less at LH surge)
- Two retrospective studies found no association with endometrial compaction and live birth rates
Natural proliferative phase (NPP) FETs
Finally, the researchers looked at natural proliferative phase (NPP) FETs.
This is a newer approach where the endometrium develops naturally during the first half of the cycle, but progesterone is started once the lining reaches an adequate thickness (typically ≥7 mm), without relying on ovulation for timing. Embryo transfer is then timed based on a set number of days of progesterone exposure (eg. P+5 for blastocysts), similar to a medicated FET. The idea is to combine the more natural hormonal environment of a natural cycle with the scheduling flexibility of a medicated cycle.
In this study, they combined data to compare NPP FETs with natural FETs and medicated FETs.
- NPP FET was associated with a 25% higher relative live birth rate compared to medicated cycles (relative risk [95% CI]: 1.25 [1.13–1.38], 3 non-randomized studies, I2= 5.36%)
- There were no differences in live birth between NPP and natural FETs
Conclusion
This review shows that while natural cycle FETs are widely used, many parts of how they’re done aren’t well supported by strong evidence.
Key takeaways include:
- For true natural FETs, ovulation timing based on LH alone may not be reliable, and combining methods like progesterone or ultrasound may be more accurate
- LUF occurs in about 13% of cycles and may lower success in true natural FETs, though results are mixed
- Luteal phase support seems helpful in true natural cycles but not in modified natural cycles
- Modified natural cycles allow for flexible trigger and transfer timing
- NPP FET shows similar outcomes to natural cycles and possibly better outcomes than medicated cycles, but data is limited
Most of the evidence comes from non-randomized studies, with few randomized trials, and more high quality studies are needed to better guide practice.
Want to read more about natural FETs?
The post discusses various frozen embryo transfer protocols, which includes a medicated FET, natural cycle FET (true natural/modified natural), and mild ovarian stimulated FET, along with their scheduling. In addition, it examines whether one FET protocol is superior to another, the relevance of the corpus luteum in medicated vs natural cycle FETs, and optimal progesterone levels. Read more.
A 2025 randomized controlled trial found that natural cycle FETs led to higher live birth rates and fewer miscarriages than medicated FETs in ovulatory women with a good prognosis. Read more.
A 2026 randomized trial found that natural FETs had similar healthy live birth rates to medicated FETs, but were linked to lower risks of preeclampsia, pregnancy loss, and some other pregnancy complications. Read more.
Researchers in a 2023 study found decreased adverse pregnancy and neonatal outcomes in those who performed a natural vs medicated FET, including abnormal birth weights, preeclampsia, preterm births, and more. Read more.
Reference
About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.