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Comparative Study
. 2014 Jun;101(6):1724-31.
doi: 10.1016/j.fertnstert.2014.02.027. Epub 2014 Mar 29.

Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus ανβ3 testing in women with unexplained infertility

Jason M Franasiak  1 , Kristin J Holoch  2 , Lingwen Yuan  3 , David P Schammel  4 , Steven L Young  3 , Bruce A Lessey  5
Affiliations
Comparative Study

Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus ανβ3 testing in women with unexplained infertility

Jason M Franasiak et al. Fertil Steril. 2014 Jun.

Abstract

Objective: To evaluate endometrial leukemia inhibitor factor (LIF) expression as a marker of endometrial receptivity in women with unexplained infertility (UI).

Design: Prospective case-control study.

Setting: University-associated infertility clinics.

Patient(s): Women with UI for more than 1 year and healthy control women.

Intervention(s): Endometrial biopsy.

Main outcome measure(s): Time to pregnancy was compared between patients with UI who were evaluated for endometrial LIF protein as well as ανβ3 integrin expression. Endometrium was evaluated using immunohistochemistry (IHC) and messenger RNA by real time reverse transcriptase-polymerase chain reaction (PCR) (quantitative real-time reverse transcriptase-PCR) in samples from women with UI as well as healthy control women.

Result(s): Leukemia inhibitor factor was expressed in epithelial cells in a cyclic fashion in controls, and overall expression in the secretory phase was similar between controls and women with UI, whereas ανβ3 integrin expression was reduced. However, using quantitative real-time PCR, LIF messenger RNA abundance was 4.4-fold lower in women with low levels of ανβ3 integrin expression compared with samples with normal integrins. By immunohistochemistry, ανβ3 integrin expression was always lacking when the histology was out of phase, whereas LIF expression was only negative in a subset of those samples. Reduced endometrial LIF expression was strongly associated with poor reproductive outcomes.

Conclusion(s): Endometrial LIF expression peaks in the midsecretory phase and is reduced in some women with UI. The use of LIF in combination with ανβ3 integrin as biomarkers appears to be superior to integrin testing alone when evaluating endometrial receptivity, primarily because of its earlier pattern of expression during the secretory phase.

Keywords: Implantation; LIF; endometriosis; endometrium; leukemia inhibitory factor.

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Figures

Figure 1
Figure 1
Expression of leukemia inhibitor factor (LIF) in controls and subjects with unexplained infertility (UI). (A) Leukemia inhibitor factor-positive immunostaining showing luminal staining (inset) on the uterine projections. This pattern was seen more often in controls compared with patients with UI. (B) An example of negative LIF immunostaining in a woman with UI. (C) Using quantitative real-time polymerase chain reaction (PCR) for LIF expression, the cycle dependence of LIF is seen in healthy controls from the proliferative and midsecretory phase (left side; P=.03). The LIF expression was also compared in the midsecretory phase of women with UI and known endometriosis. Those women with low integrin expression also exhibited depressed LIF expression, whereas those with normal integrin (NI) expression had higher levels of LIF messenger RNA expression (right side; P=.004).
Figure 2
Figure 2
(A) Time to pregnancy using Kaplan Meier survival analysis based on β3 integrin subunit protein expression alone was significantly different between those women who did or did not express this biomarker by immunohistochemistry (P<.01). (B) When leukemia inhibitor factor (LIF) expression was included along with the β3 integrin subunit, those women who expressed LIF were similar to those who expressed the β3 integrin subunit, but very few subjects successfully conceived (2) when both biomarkers were reduced (P=.02). One subject conceived in the month of biopsy sampling and another woman, in an unmonitored cycle 12 months after the biopsy.
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