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. 2020 Jul-Aug;34(4):1951-1963.
doi: 10.21873/invivo.11992.

Endometrial Dating Method Detects Individual Maturation Sequences During the Secretory Phase

Joachim Alfer  1   2 , Amir Fattahi  3   4 , Nathalie Bleisinger  3 , JÜrgen Krieg  5 , Rolf Behrens  6 , Ralf Dittrich  3 , Matthias W Beckmann  3 , Arndt Hartmann  7 , Irmgard Classen-Linke  8 , Roxana M Popovici  9
Affiliations

Endometrial Dating Method Detects Individual Maturation Sequences During the Secretory Phase

Joachim Alfer et al. In Vivo. 2020 Jul-Aug.

Erratum in

  • Erratum.
    [No authors listed] [No authors listed] In Vivo. 2020 Sep-Oct;34(5):3055. In Vivo. 2020. PMID: 32871852 No abstract available.

Abstract

Background/aim: This study assessed whether a new immunohistochemical dating method allows precise endometrial dating allowing optimal timing for embryo transfer.

Patients and methods: A novel method was used for endometrial dating, with parameters including menstrual cycle days, Noyes histological criteria, along with immunohistochemical expression pattern of estrogen and progesterone receptors and proliferation marker Ki-67. Endometrial maturation was analyzed on days +5 to +10 after ovulation or progesterone administration in 217 biopsies from 151 subfertile patients during the secretory phase.

Results: Endometrial maturation varied individually, occurring 1.68±1.67 days late. Comparison of histological maturation with clinical days after ovulation showed a delay of about 2 days.

Conclusion: Endometrial maturation requires 8 days, rather than the expected 6 days, to reach the histological mid-secretory phase. This is not a delay and is also seen in fertile patients. The new analysis method used is superior to that using Noyes criteria alone and provides a better basis for determining conditions for optimal timing of embryo transfers.

Keywords: Endometrial dating; endometrial receptivity; estrogen receptor; progesterone receptor; window of implantation.

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Conflict of interest statement

The Authors have no conflicts of interest to declare

Figures

Figure 1
Figure 1. Hematoxylin-eosin staining for histological analysis of the endometrium on days 16-24 of the menstrual cycle, with key features under Noyes criteria. Key features: Day 16: Subnuclear vacuolation of the glandular epithelium is regular and becomes prominent, pseudostratification of the nuclei is still visible in the glandular epithelium, and stroma is dense with nearly naked nuclei. Day 17: Only focal stratification of the glandular epithelium is present, nuclei are more or less in a row, with homogeneous cytoplasm above them and large vacuoles below. Day 18: There is almost no stratification of the glandular epithelium. Vacuoles have decreased in size and slip past the nucleus into the cytoplasm nearer the glandular lumen and thence into the lumen. Day 19: Few vacuoles remain. Superficially, this phase may resemble the early vacuolation of the 16-day phase. The presence of intraluminal secretion and absence of pseudostratification and of mitoses serve to characterize it. Day 20: Secretion reaches its peak. Subnuclear vacuoles are rare and the nuclei are round and basally located. Secretion, positively stained with periodic acid-Schiff reaction (red colour), becomes prominent and is visible until day 25. Start of stromal edema. Day 21: Stromal edema increases. Day 22: Stromal edema reaches its peak. The spiral arterioles are not prominent, and stromal cells are nearly naked nuclei, with only thin cytoplasm. Day 23: Spiral arterioles become prominent due to condensation of their surrounding stroma. The nuclei and the cytoplasm of the periarteriolar stromal cells become larger. This is the earliest predecidual reaction. Day 24: Spiral arterioles become prominent due to the pre-decidual reaction around them. Pre-decidual changes start to differentiate focally under the surface epithelium. This is normally expected at day 25 by Noyes criteria, but in the present study it was seen irregularly in combination with pre-decidual reactions around spiral arterioles, suggesting that it starts on day 24. Stromal proliferation resumes. Magnification: Main image ×100; inset: ×400.
Figure 2
Figure 2. Immunohistochemical staining of estrogen receptor (A) progesterone receptor (B) and Ki-67 (C) in the endometrium on days 16-24 of the menstrual cycle. Magnification, main image: ×100, and inset: ×400
Figure 2
Figure 2. Immunohistochemical staining of estrogen receptor (A) progesterone receptor (B) and Ki-67 (C) in the endometrium on days 16-24 of the menstrual cycle. Magnification, main image: ×100, and inset: ×400
Figure 2
Figure 2. Immunohistochemical staining of estrogen receptor (A) progesterone receptor (B) and Ki-67 (C) in the endometrium on days 16-24 of the menstrual cycle. Magnification, main image: ×100, and inset: ×400
Figure 3
Figure 3. Percentage of immunohistochemically positively stained nuclei of endometrial glandular epithelial cells for estrogen (ER) and progesterone (PR) receptors, and Ki-67 for immunohistological days 16-24 in natural cycles and hormone replacement therapy (HRT) cycles. A: ER and PR expression in natural cycles. B: ER and PR expression in HRT cycles. C: Ki-67 expression in natural cycles. (D) Ki-67 expression in HRT cycles
Figure 4
Figure 4. Endometrial dating according to the novel dating method during natural cycles. Dating was performed on biopsies from ovulation (OV) days +5 (A), +6 (B), +7 (C), +8 (D), +9 (E), and +10 (F). WOI: Window of implantation
Figure 5
Figure 5. Endometrial dating according to the novel dating method on days 5 (A) and 10 (B) after progesterone (P) in hormone replacement therapy (HRT) cycles. WOI: Window of implantation
Figure 6
Figure 6. Comparison of immunohistological endometrial dating (novel method) with clinical days after ovulation (OV)
See this image and copyright information in PMC

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