Delayed Implantation Window is Common in Natural Cycles

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Delayed implantation window is common in natural cycles

Endometrial delay is found to be part of a normal individual dynamic transformation process

doi.org/10.1007/s00404-021-06086-8

Background

Inadequate endometrial receptivity is believed to be responsible for up to two thirds of unsuccessful embryo transfers in IVF / ICSI (in vitro fertilization / intracytoplasmic sperm injection).

Ultrasound confirmation of trilaminar (triple-line) endometrial pattern and thickness > 7mm is routinely associated with good endometrial quality for successful implantation however histomorphological dating, as per Noyes et al. is still the regarded as the gold standard for endometrial dating.

Given subfertile patients may have inadequate endometrial receptivity, testing this hypothesis using histological dating could provide new evidence on the optimal timing for embryo transfer.

Aim

To assess any differences in the opening or closing of the implantation window during the secretory phase of individuals via monitoring of endometrial transformation rates, on expected day of embryo transfer (5DPO, 5 days past ovulation) and final day of implantation window (10DPO, 10 days past ovulation).

Methodology

This study consisted of 76 women on natural mock cycles, and 58 women on hormone replacement therapy (HRT) mock cycles. Mean age of women was 37.7 ±3.8 years and 36.5 ±4.6 years respectively.

All women had adequate ovulation, normal hormone levels and displayed the triple-line endometrial pattern on ultrasound. Women with abnormal uterine cavities or endometrial thickness ≤ 6mm were excluded from the study to minimise potential bias.

Endometrial biopsies were collected from each woman during the mock cycle, on ovulation / progesterone day + 5 days (1st sample) and ovulation / progesterone day + 10 days (2nd sample), in woman on natural / HRT cycles, corresponding to menstrual cycle days 19 and 24.

All cycle day 24 biopsy samples were taken from a different area in the uterine cavity to avoid conflicting results.

Endometrial dating was then performed using a combination of menstrual cycle days, histological dating (as per Noyes protocol) and immunohistochemical expression analysis of estrogen and progesterone receptors along with proliferation marker Ki-67.

Results

Initial analysis of 268 biopsy samples showed a diverse range of delayed, constant (normal) and accelerated endometrial development, however in the majority of cases endometrial transformation was delayed and not associated with age.

Among natural cycles, only 3/76 and 13/76 samples, on first and second biopsies, were at expected endometrial transformation dates respectively. Likewise in HRT cycles, only 2/58 and 10/58 samples, in first and second biopsies, were at expected endometrial transformation dates. Accelerated development was more rare and found only in 3 women, on initial biopsy, and 7 women on second biopsy, from the 134 women in total.

Endometrial transformation dating among women in Natural cycles

Natural cycle1st Sample (5DPO)2nd Sample (10DPO)
4 days – Delay5.3%2.6%
3.5 days – Delay0.0%1.3%
3 days – Delay28.9%10.5%
2.5 days – Delay3.9%2.6%
2 days – Delay31.6%27.6%
1.5 days – Delay2.6%2.6%
1 day – Delay21.1%34.2%
No Delay3.9%17.1%
1 day – Early2.6%1.3%

Endometrial transformation dating among women in HRT cycles

HRT cycle1st Sample (5DPO)2nd Sample (10DPO)
5 days – Delay0.0%1.7%
4 days – Delay5.2%3.4%
3.5 days – Delay0.0%3.4%
3 days – Delay19.0%8.6%
2.5 days – Delay0.0%3.4%
2 days – Delay53.4%20.7%
1.5 days – Delay0.0%1.7%
1 day – Delay17.2%29.3%
No Delay3.4%17.2%
1 day – Early1.7%10.3%

Statistical analysis of the data showed the mean delay in natural cycles was 2.05 ±1.39 (ovulation + 5 days) and 1.45 ±0.97 (ovulation + 10 days). Similarly the mean delay in HRT cycles was 2.0 ±0.94 (progesterone + 5 days) and 1.32 ±1.37 (progesterone + 10 days).

In natural cycles further analysis for changes in delay, between first and second samples, showed that 28.9% of women had a constant delay, 48.7% a reduction in delay and 23.4% had an increase in delay. Similarly in HRT cycles, 17.3% of women had a constant delay, 56.9% a reduction in delay and 25.8% had an increase in delay, at the time of second biopsy.

Interestingly individual analysis of biopsy results showed that 3/76 women under natural cycle, had naturally fast endometrial transformation (8 histomorphological days in only 5 cycle days), while in HRT cycles, 5/58 women also had fast endometrial transformation.

None of the second biopsies showed fibrous changes or enhanced vascularization meaning no follow up biopsies were taken from previous locations.

The authors concluded a disturbed progesterone-related regulatory process may be the cause of this dysschronization, between the embryo and endometrium, given this delay in endometrial transformation was also seen in progesterone administered HRT cycles.

SUMMARY: CAN THE EMBRYO IMPLANT LATE

In this study and others, 46% of subfertile women & 26% of fertile women showed a delay in the opening (5DPO) & closing (10DPO) of their embryo implantation window ≥ 2 days, suggesting a significant number of embryos do implant late naturally according to Noyes original criteria.

Limitations

  1. Results are not representative of stimulated IVF cycles given ovarian stimulation alters the protein expression profile in endometrial secretion.
  2. Embryo transfer was not performed, following individual endometrial receptivity profiling, to further substantiate clinical relevance.

Funding

This study was supported by Erlangen University Hospital and Projekt DEAL.

Glossary

Histological
The study of the structure of cells and tissue under a microscope.

Histomorphological
Use of histology to study the morphology of normal or abnormal tissues.

Immunohistochemical
A laboratory method that uses antibodies to check for antigens (markers) in a sample of tissue.

Proliferation marker
Markers that are commonly used to assess the growth fraction of a cell population.

Receptivity
A physiological state in which the endometrium acquires an adhesive phenotype permitting embryo implantation.

Receptor
Chemical structures, composed of protein, that receive and transduce signals within a biological system.

Secretory phase
The stage of the menstrual cycle immediately following ovulation.

Trilaminar (triple-line)
Three defined lines outlining three laminae (layers) in the uterus.

Vascularization
The formation of blood vessels and capillaries in living tissue.

Similar studies

Alfer J, et al. (2020). Endometrial dating method detects individual maturation sequences during the secretory phase. https://doi.org/10.21873/invivo.11992

Díaz-Gimeno P, et al. (2012). The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. https://doi.org/10.1016/j.fertnstert.2012.09.046

Coutifaris C, et al. (2004). Histological dating of timed endometrial biopsy tissue is not related to fertility status. https://doi.org/10.1016/j.fertnstert.2004.03.069

Murray M J, et al. (2004). A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. https://doi.org/10.1016/j.fertnstert.2003.11.030

Zawar M P, et al. (2003). Histopathological study of endometrium in infertility. https://pubmed.ncbi.nlm.nih.gov/15025360/


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